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Patent application title:

GAMBOGIC ACID CYCLIZATION ANALOGUES, THEIR PREPARATION METHOD AND APPLICATION THEREOF

Publication number:

US20130039904A1

Publication date:

2013-02-14

Application number:

13/389,263

Filed date:

2010-08-02

Abstract:

The present invention discloses a gamboge acid cyclization analogs, their preparation methods and applications by semi-synthesis with the following structural formula I-III:

Where ring A, ring B or/and ring C is 4-10 membered saturated or/and unsaturated aliphatic ring aliphatic heterocycle or aryl heterocycle. R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁or/and R₁₂is, independently at each occurrence, optionally substituted substituent of glycosyl, multi-hydroxyl, amino acid, acyloxy, phosphoric acid oxy, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy, thiol, aliphatic or cyclic group containing oxygen, sulfur, nitrogen or phosphorus, one of the substituents or combinations thereof.

The present invention has antitumor activity management, antiviral, antibacterial and antifungal activity management, as anti-tumor, anti-viral, immune, antibacterial and antifungal agents, with other known anti-tumor, anti-viral, immune, together with the application of antibacterial and antifungal.

Inventors:

Lifeng Xu 8 🇺🇸 San Diego, CA, United States

Assignee:

Liaoning Lifeng Scientific & Technology Development Company Ltd. 1 🇨🇳 Liaoning, China

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Classification:

A61K31/4188 » CPC further

Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole 1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil

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Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings

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Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals Heterocyclic radicals containing only oxygen as ring hetero atoms

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Medicinal preparations containing organic active ingredients; Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline

A61K31/7048 IPC

Medicinal preparations containing organic active ingredients; Carbohydrates; Sugars; Derivatives thereof; Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

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C07D491/22 » CPC further

Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups - , , or in which the condensed system contains four or more hetero rings

A61K31/436 IPC

Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin

A61K31/519 IPC

Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two nitrogen atoms as the only ring heteroatoms, e.g. piperazine; Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

C07D493/18 IPC

Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings Bridged systems

A61K31/496 IPC

Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two nitrogen atoms as the only ring heteroatoms, e.g. piperazine Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene

A61K31/5377 IPC

Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

C07D498/22 IPC

Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

A61K31/5365 IPC

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C07F9/6561 » CPC main

Compounds containing elements of Groups 5 or 15 of the Periodic System; Phosphorus compounds; Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Medicinal preparations containing organic active ingredients; Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

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Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups , or - in which the condensed system contains four or more hetero rings

A61K31/554 IPC

Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem

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Medicinal preparations containing organic active ingredients; Carbohydrates; Sugars; Derivatives thereof; Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

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Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals Acyclic or carbocyclic radicals, substituted by hetero rings

Description

THE FIELD OF INVENTION

This invention relates with anti-tumor activities, medicinal chemistry research and preparative methods of new cyclized gambogic acid derivatives and analogs thereof. The invention also relates with the medication applications of anti-tumor and other diseases by this kind of compounds.

BACKGROUND OF THE INVENTION

This invention is in the field of medicinal chemistry. In particular, the invention relates with cyclized gambogic acid derivatives and analogs, and the discovery of these compounds is therapeutically effective anti-cancer agents.

DESCRIPTION OF BACKGROUND ART

Medicinal plant Gamboge is a gel resin from trees of Hai teng, Yu huang, Yue huang and La huang, in India, Thailand, the islands of Southeast Asia, Cambodia, Thailand, Viet Nam and China (Ref. 1: Wang Ming, Feng Xu, Zhao Youyi, Fu Hui, Studies and Application of Gamboge, Chinese Medicine Research and Chinese Wild Plant Resources, 2003, 22 (1), 1-3).

Gambogic resin contains gambogic acid, neogambogic acid, allogambogic acid and other ingredients. Anti-cancer effects of gambogic acid was proved by the experiments of Chinese research group (Ref. 2: Xiang S. R., Chen T K, Huang, Y. C. et al, Effect on tumor S₁₈₀and ascites by gambogic acid, J. Acta Acad Med Jiang xi, 1981, (1), 172211). Recent study showed the effect of gambogic acid on pancreatic cancer cells (Ref. 3: Qidong You, et al, Chinese patent CN1309125A). Shu Long, Wang reported a prodrug of gambogic acid reacted with multi-ethyleneglycol (Ref. 4: Shulong, Wang, A new gambogic acid derivative, Chinese Patent Application CN 1563014A). While Wen-Hu, Duan, et al, reported the structural modifications of C-4 and C-30 of gambogic acid [CN 1715283]. The patents, WO 06/44216, U.S. Pat. No. 7,176,234, U.S. Pat. No. 7,138,620, U.S. Pat. No. 7,138,428, U.S. Pat. No. 6,613,762, U.S. Pat. No. 6,462,041, US 2005/00040206, US 2004/0082066, US 2003/0078292 and US 2002/0076733 reported the structural modification of gambogic acid, chemical synthesis, preparation and study of anti-tumor activity at sites of C-10 and C-30.

To date there has been no report related with structural modification of gambogic acid with the introduction of ring structure to form cyclized gambogic acid derivatives and analogs at C-4, C-6, C-8 or C-10 site, nor structure-activity relationship studies by the introduction of ring system from all literature reported.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the inhibition growth of sarcoma S₁₈₀anatomy (Kunming mice inoculated with S₁₈₀administered 7 days) of 11 compounds.

SUMMARY OF THE INVENTION

This invention relates with the cyclized gambogic acid derivatives and analogs by the cyclization of gambogic acid, their preparation method, and the discovery of therapeutically effective anti-cancer. Their structures are formula I, II and III.

or stereoisomers, tautomers, prodrug, pharmaceutically acceptable salts, complex salts or solvates thereof, wherein:

The dotted lines are optionally substituted single bonds, optionally substituted double bond or a optionally substituted heterocyclic group containing carbon, oxygen, sulfur or nitrogen element;

Ring A, ring B or/and ring C is 4-10 membered saturated or/and unsaturated aliphatic ring aliphatic heterocycle or aryl heterocycle.

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁or/and R₁₂is, independently at each occurrence, optionally substituted substituent of glycosyl, optionally substituted multi-hydroxyl, amino acid, acyloxy, phosphoric acid oxy, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy, thiol, substituted thiol, aliphatic or cyclic group containing primary amine secondary amine or/and tertiary amine or substituted primary amine, substituted secondary amine or substituted tertiary amine, where contains optionally substituted one or combination;

Substituent containing oxygen, sulfur, nitrogen or phosphorus element is, independently at each occurrence, optionally substituted one or combination of saturated, unsaturated C_1-10alkyl, optionally substituted 1-4 double bond, optionally substituted triple bond, optional substituent of saturated or unsaturated C_1-10alicyclic, arylcyclic and heterocyclic group, where contains a cycle or combination of oxygen, sulfur, nitrogen or phosphorus element, saturated or unsaturated 3-7 membered alicycle, aryl cycle, multi-cycle, aliphatic heterocycle, aryl heterocycle or fused heterocycle;

wherein:

- X₁and X₂are, independently at each occurrence, C═O, C═Rb—Ra, CHOH, CHORb, CHRb or substituent, where Rb contains, independently at each occurrence, one or combination of C, N or P element; Ra is H, H₂, optionally substituted straight-alkyl, optionally substituted branched-alkyl, C_1-10optionally substituted saturated alkyl, optionally substituted 1-4 double bond, optionally substituted 1-4 triple bond, optionally substituted unsaturated alkyl, optionally substituted saturated or unsaturated alicyclic, optionally substituted arylcyclic, optionally substituted aryl or optionally substituted 3-7 membered heterocyclic, optionally substituted aryheterocyclic, fused heterocyclic group where contains hydroxyl, halogen, oxygen, nitrogen, sulfur or phosphorus element;

Substituent is, independently at each occurrence, C_1-10optionally substituted saturated Glycosyl is D- or L-configuration and its glycoside bond is C—C or C-hetero bond connection, including 1-8 optionally substituted glycosyl or optional substituent glycosyl group;

Multi-hydroxyl is, independently at each occurrence, 1-10 optionally substituted hydroxyl group of alkyl, aryl, cyclic or heterocyclic group, where contains optionally substituted or combination of amino acid, acyloxy, sulfonyloxy, phosphoric acid oxy, alkoxy, aryoxyl or heterocyclicoxyl, thiol, substituted thiol, or heteroatom contained alkyl, alicyclic, aryl ring, aliphatic heterocyclic or aryl heterocyclic group;

Cyclized cyclic substituent is, independently at each occurrence, formed a new one or a combination of A-ring between C-4 and C-6, B-ring between C-6 and C-8, C-ring between C-8 and C-10 positions;

R₃is XaRa electrophilic substituent, where Xa is, independently at each occurrence, unsubstituted or substituted group containing C, S, P, and/or Si element;

R₄is, independently at each occurrence, optional substituent of 1-8 glycosyl, multi-hydroxyl, substituted multi-hydroxyl, 1-5 amino acid, 1-4 phosphate, acyloxy, phosphoric, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy, alkyl, alicyclic, aryl cyclic, aliphatic heterocyclic oxyl or aryl heterocyclic oxyl containing oxygen, sulfur, nitrogen or phosphorus element, where glycosyl, multihydroxyl, amino acid, acryloxy, phosphoryloxy, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy and substituent is the same as above.

1-8 Glycosyl is, independently at each occurrence, optionally substituted C_3-8saccharide, optionally substituted monosaccharide, optionally substituted disaccharide, optionally substituted trisaccharide and/or optionally substituted polysaccharide;

wherein:

C_3-8Saccharide is independently at each occurrence, optionally substituted C₃saccharide, optionally substituted C₄saccharide, optionally substituted C₅saccharide, optionally substituted C₆saccharide, optionally substituted C₇saccharide, optionally substituted C₈saccharide, optionally substituted hydroxyl saccharide, optionally substituted amino saccharide, optionally substituted deoxysaccharide, optionally substituted sulfuric acid saccharide, optionally substituted hetero-element saccharide and/or its glycoside.

R₇is H or XbRa; Xb is, independently at each occurrence, optional substituent containing H, C, O or N element.

wherein:

When X₁and/or X₂is C═O, C═Rb—Ra, CHOH, CHORb, or CHRb, X₁and X₂are the same or different substituents; when Rb is C, N or P element, Ra is, independently at each occurrence, optionally substituted formation of olefin, alkane, halogenated hydrocarbon, alcohol, ether, oxime, hydrazone or substituted said groups.

A bromo compound at 11-position is selected, independently at each occurrence, from: gambogic acid, methyl gambogate, ethyl gambogate, gambogyl morpholine, gambogyl.

A compound with A-ring, B-ring or/and C-ring cyclized respectively between 4- and 6-position, 6- and 8-position and 8- and 10-position of gamboge acid is selected, independently at each occurrence, from the example 1 to example 441 and the list (see claim 2) but not limiting, of the method and composition of the present invention:

fused A-ring was formed between 4- and 6-position of gambogate acid analogs; fused B-ring was formed between 6- and 8-position of gambogate acid analogs; fused C-ring was formed between 8- and 10-position of gambogate acid analogs.

A process for the manufacture of a compound of formula I, II, III comprises: for the preparation of compounds of formula I, II, III with A-ring, B-ring, C-ring and salts thereof in which the reaction of a gambogic acid or analog to introduce A-ring lactone at 4-, 6-position, B-ring at 6-, 8-position, and C-ring at 8-, 10-position forms a bond of C—C, C—O, C—S, C—N or C—P under catalysis at −78° C. to 90° C., wherein:

The reactant selected from 2-ethoxy-1-ethoxy carbon acyl-1,2-dihydroquinoline, 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyl urea hexafluorophosphate, benzotriazole N,N,N′,N′-tetramethyl urea hexafluoro phosphate, 6-chlorophenyl and triazole-1,1,3,3-tetramethyl urea hexafluoro phosphate, 1-hydroxy-7-azobis benzotriazole, 1-hydroxy-benzotriazole, 3-hydroxy-1,2,3-benzotriazin-4(3H)one, N-hydroxysuccinimide, and triethylamine, Fmoc chloride, acyl succinimide Fmoc, 9-fluorene methanol;

The catalyst selected from palladium, platinum, ruthenium, metal catalyst, organic base or inorganic base, 1-ethyl-3-(3-dimethylpropylamine)carbodiimide, ditertbutyl dicarbonate, bis(2-oxo-3-oxazoline alkyl) times phosphorus chloride, N,N′-carbonyl two pyrrolidine, N,N′-carbonyl bis (1,2,4-triazole), 6-chloro-1-hydroxybenzo triazole, N,N′-dicyclohexyl carbodiimide, 4,5-dicyano imidazole, 3-(diethoxyphosphoryl)oxy-1,2,3-benzotriazine-4-ketone, N,N′-bis isopropyl carbon imide, N,N′-diisopropyl ethylamine, 4-dimethylaminopyridine, 4,4′-dimethoxytriphenyl chloride, 4-(4,6-dimethoxytriazine)-4-methyl morpholine hydrochloride, N,N′-succinimidyl carbonate, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride;

The solvent selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexane, toluene, quinoline;

For the preparation of compounds of formula I, II, III with A-ring, B-ring, C-ring and salts, the X₁, X₂, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁or/and R₁₂is an amino acid, acyloxy, phosphoric acid, phosphoryloxy, sulfonyloxy, alkoxy, aryloxy, heterocyclicoxy, hydrocarbons, alicyclic, glycosyl, multi-hydroxyl, carboxyl, glucosyl, multi-hydroxyl, alkane, aryl, alicyclic, heterocyclic, heteroarylcyclic or substituent modified by acylation, halogenation; electrophilic substituent at 9-position, nucleophilic substituent at 10-position accompanied by 1,4 addition reaction; allylation at 11-position, 26-position, 31-position or 36-position with a bond of C—C, C—O, C—S, C—N or C—P under catalysis at −78° C. to 90° C.

A method for treating cancer, comprising: administration to a above compound, in the range of 0.001 mg/kg-250 mg/kg, a pharmaceutically acceptable salt or prodrug from thereof; a cancer is selected from the lung cancer, stomach cancer, colon cancer, small cell lung cancer, thyroid cancer, esophageal cancer, pancreatic cancer, endometrial cancer, adrenal cortical carcinoma, head and neck cancer, Osteogenic sarcoma, breast cancer, ovarian cancer, Vail Williams tumors, cervical tumors, testicular cancer, genitourinary cancer, skin cancer, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdomyosarcoma, Kaposi sarcoma, malignant melanoma, malignant pancreatic islet tumors, non-Hodgkin's lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, malignant carcinoid cancer, choriocarcinoma, acute and chronic lymphocytic leukemia, primary macroglobulinemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, or Hodgkin's disease.

The compound is administered together with at least one known cancer, chemotherapeutic and immune agent selected from cyclophosphamide, vincristine, busulfan, vinblastine, cisplatin, carboplatin, mitomycin C, doxorubicin, colchicine, etoposide, paclitaxel, docetaxel, camptothecin, topotecan, arsenic trioxide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2-deoxyuridine, hydroxyurea, thioguanine, melphalan, chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, octreotide, retinoic acid, tamoxifen, doxazocin, terazosin tamsulosin, tamsulosin, fluorine pyridinoline, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, atorvastatin, amprenavir, abacavir, flavonoids pyridinoline, ritonavir, saquinavir, rofecoxib, alanosine, retinal, tretinoin tocoferil, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethyl ornithine, fenretinide, N-4-carboxyphenyl retinamide, genistein, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232, 632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778, 123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine, Valecoxib.

The compound is selected from the exemplified examples or stereoisomers, tautomers, pharmaceutically acceptable salts, inorganic acid salt, organic acid salt, organic basic salt, organic basic salt, complex salt, prodrug or solvates thereof in association with a pharmaceutically acceptable excipient or carrier.

A compound for treating, preventing or slowing the progression of neoplasia and cancer, and infection diseases by virus, bacterial or fungi, including bacterial infections and fungal infections of the drug application, which comprises administration together with at least one known chemotherapeutic agent selected from the group consisting of antibacterial and antifungal drugs to a patient in need of such treatment.

The administration may be by oral route, parenteral, subcutaneous, intravenous, intramuscular, intra-peritoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.

The invention has the following beneficial effects: the structure-activity relationship studies have shown that toxicity and activity of gambogic acid cyclization analogs are sensitive by the introduction of the A ring, B-ring and C-ring cyclization at the 4-, 6-position, 6-, 8-position and 8-, 10-position. The inhibition rate increased to 25-55% after modification of gambogic acid into cyclized gambogic acid analogs.

Gambogic acid preparation (see U.S. Patent Publication No. US2011/0038952A1)

Chemical Synthesis

Synthesis of Gambogic Acid Analogies at 30-Position into the Ester, Anhydride and Amide:

gambogic acid was modified into the analogs of esters, anhydrides and amides by the catalyst to form C—O bond, C—S bond, C—N bond, C—P bond and the solvent selected from THF, 1,4-dioxane, Acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, n-hexane, toluene, quinoline, at −78 to 90° C.

The Introduction of the A-Ring Analogs:

cyclized gamboge acid analogs were modified by the introduction of the A-ring between 4- and 6-position by the catalyst to form C—C bond, C—O bond, C—S bond, C—N bond, C—P bond and the solvents selected from THF, 1,4-dioxane, acetonitrile, dichloromethane, N,N-dimethyl formamide, N,N-dimethylacetamide, n-hexane, toluene, quinoline, at −78 to 90° C.

The Introduction of the B-Ring Analogs:

cyclized gamboge acid analogs were modified by the introduction of the A-ring between 6- and 8-position by the catalyst to form C—C bond, C—O bond, C—S bond, C—N bond, C—P bond and the solvents selected from THF, 1,4-dioxane, acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, n-hexane, toluene, quinoline at −78 to 90° C.

The Introduction of the C-Ring Analogs:

cyclized gamboge acid analogs were modified by the introduction of the C-ring between 8-, 10-position by the catalyst to form C—C bond, C—O bond, C—S bond, C—N bond, C—P bond and the solvents selected from THF, 1,4-dioxane, acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, n-hexane, toluene, quinoline at −78 to 90° C.

Modification of Gambogic Acid Analogs at 6-Position:

Modification of gambogic acid analogs at 6-position by introduction of ester, anhydride, amide, ether, sugar, substituted sugar or multi-hydroxyl groups to form C—C bond, C—O bond, C—S bond, C—N bond and C—P bond by the catalyst selected from silver-containing catalyst, Lewis acid, perchloric acid and molecular sieves.

The phenolic hydroxyl of gambogic acid analogs at 6-position can be made into a good leaving and then the cyclized gambogic acid analogs was modified by the introduction of a nucleophilic agent to form C-halogen bond, C—C bond, C—S bond, C—N bond and/or C—P bond analogs;

The following examples are illustrative, but not limiting, of the method and composition of the present invention.

EXAMPLES

Synthesis and Preparation

The following examples illustrate the present invention. If no mentioned otherwise, the reactions take place at room temperature.

Example 1

Compound 1.1 in Table 1

To a mixture of gamboge acid 12.56 g (20 mmol), catalyst volume DMAP in THF 80 ml and DMF 20 ml was added ethanolamine 1.22 g (20 mmol). The mixture was stirred at room temperature 8 h and added glacial acetic acid 1.3 ml, at 40° C., for 8 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 1.1, IR (KBr, cm⁻¹): 3422, 2965, 2925, 2855, 1738, 1711, 1633, 1594, 1508, 1439, 1400, 1384, 1332, 1174, 1136, 1048, 957, 793, 772.

Example 2

Compound 1.2 in Table 1

To a mixture of compounds 1.1 7.13 g (10 mmol) and triethylamine 1.52 g (15 mmol) in CH₂Cl₂30 ml, in THF 80 ml and DMF 20 ml was added 4-O-D-allosylbenzoyl chloride 4.77 g (15 mmol). The mixture was stirred at room temperature for 8 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 1.2, IR (KBr, cm⁻¹): 3420, 2925, 2855, 1738, 1633, 1594, 1508, 1457, 1438, 1383, 1332, 1175, 1136, 1048, 793, 771, 496.

Example 3

Compound 1 in Table 1

To a 125 ml round bottom flask was added 3.51 g (3 mmol) compound 1.2 in methanol 50 ml and the mixture was refluxed 14 hours. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 1, IR (KBr, cm⁻¹): 3421, 2968, 2926, 1739, 1711, 1633, 1607, 1544, 1502, 1458, 1438, 1398, 1328, 1299, 1241, 1176, 1082, 1042, 906, 848, 768, 560; ¹H NMR (CDCl₃) δ 8.20 (d, J=8.4 Hz, 2H), 7.36 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.44 (d, J=10.2 Hz, 1H), 6.39 (t, J=6.0 Hz, 1H), 5.60 (d, J=9.6 Hz, 1H), 5.36 (d, J=7.2 Hz, 1H), 5.22 (m, 1H), 5.07 (m, 1H), 4.25 (m, 1H), 3.93 (d, J=11.4 Hz, 1H), 3.86 (m, 1H), 3.81 (m, 1H), 3.71˜3.66 (m, 5H), 3.43 (m, 1H), 3.38 (m, 1H), 3.37 (m, 1H), 2.64 (Br, 5H), 2.51 (d, J=9.0 Hz, 1H), 2.29 (m, 1H), 2.05 (m, 2H), 1.78 (s, 3H), 1.76 (m, 2H), 1.72 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H), 1.59 (s, 3H), 1.36 (s, 3H), 1.40 (m, 1H), 1.29 (s, 3H).

Example 4

Compound 2.1 in Table 1

To a mixture of methyl gambogate 12.84 g (20 mmol) and ammonium acetate 3.85 g (50 mmol) in DMF 60 ml, was added 1,3-indanedione 3.50 g (24 mmol). The mixture was stirred at 35° C. for 24 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 2.1, IR (KBr, cm⁻¹): 3438, 2971, 2925, 2856, 1741, 1710, 1644, 1627, 1586, 1456, 1438, 1375, 1321, 1254, 1216, 1176, 1125, 965, 947, 906, 839, 754.

Example 5

Compound 2.2 in Table 1

To a mixture of compound 2.1 3.35 g (5 mmol) and triethylamine 0.71 g (7 mmol) in CH₂Cl₂20 ml was added 4-O-D-Allosylbenzoyl chloride 2.23 g (7 mmol). The mixture was stirred at rt for 24 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 2.2, IR(KBr, cm⁻¹): 3437, 2964, 2928, 1752, 1712, 1676, 1632, 1606, 1508, 1462, 1435, 1373, 1321, 1229, 1173, 1092, 1065, 1045, 948, 910, 759, 690.

Example 6

Compound 2 in Table 1

To a compound 2.2 2.45 g (2 mmol) was added methanol 30 ml. The mixture was refluxed for 14 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 2, IR (KBr, cm⁻¹): 3437, 2924, 2854, 1741, 1708, 1674, 1641, 1604, 1509, 1461, 1384, 1320, 1259, 1171, 1041, 906, 846, 804, 690, 621. ¹H NMR (CDCl₃) δ 7.97 (m, 2H), 7.79 (m, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.57 (d, J=10.2 Hz, 1H), 6.39 (t, J=6.0 Hz, 1H), 5.38 (d, J=10.2 Hz, 1H), 5.22 (d, J=7.2 Hz, 1H), 5.02 (m, 1H), 4.92 (m, 1H), 4.25 (m, 1H), 4.19 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 3.63 (s, 1H), 3.59 (m, 3H), 3.40 (m, 1H), 3.20 (m, 1H), 3.19 (m, 1H), 2.75 (m, 2H), 2.51˜2.50 (br, 4H), 2.39 (d, J=8.4 Hz, 1H), 2.00 (m, 1H), 1.97 (m, 2H), 1.95 (s, 3H), 1.78 (s, 3H), 1.70 (m, 1H), 1.66 (m, 6H), 1.57 (s, 3H), 1.52 (m, 2H), 1.34 (s, 3H), 1.38 (s, 3H), 1.17 (s, 3H).

Example 7

Compound 3.1 in Table 1

To a mixture of 4-O-D-Allosylbenzoyl chloride 9.48 g (20 mmol), DMAP 1.22 g (10 mmol), THF 30 ml and DMF 10 ml, was added ethanolamine 2.44 g (40 mmol). The mixture was stirred at room temperature 4 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 3.1, IR (KBr, cm⁻¹): 3432, 2919, 2850, 1734, 1699, 1628, 1603, 1583, 1565, 1506, 1468, 1413, 1384, 1306, 1283, 1229, 1166, 1144, 1097, 1037, 838, 720.

Example 8

Compound 3.2 in Table 1

To a mixture of compound 3.1 5.17 g (10 mmol) and gambogic acid 12.56 g (20 mmol) in THF 80 ml and DMF 20 ml, was added DMAP 0.61 g (5 mmol). The mixture was stirred at room temperature 8 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 3.2, IR (KBr, cm⁻¹): 3445, 2925, 2855, 1748, 1663, 1633, 1606, 1508, 1459, 1384, 1320, 1227, 1173, 1141, 1089, 1044, 910, 851, 760, 617.

Example 9

Compound 3 in Table 1

To a compound 3.2 2.25 g (2 mmol) was added methanol 30 ml. The mixture was refluxed for 8 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 3, IR (KBr, cm⁻¹): 3347, 2967, 2924, 2856, 1739, 1716, 1664, 1628, 1609, 1522, 1503, 1453, 1375, 1323, 1224, 1175, 1125, 1060, 1045, 955, 907, 830, 748, 599. ¹H NMR (CDCl₃) δ 11.92 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.57 (d, J=10.2 Hz, 1H), 6.49 (t, J=6.0 Hz, 1H), 5.38 (d, J=10.2 Hz, 1H), 5.22 (d, J=7.2 Hz, 1H), 5.02 (m, 1H), 4.92 (m, 1H), 4.25 (m, 1H), 4.19 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 3.61 (m, 3H), 3.40 (m, 1H), 3.20 (m, 1H), 3.19 (m, 1H), 2.75 (m, 2H), 2.51˜2.50 (m, 3H), 2.39 (d, J=8.4 Hz, 1H), 2.00 (m, 1H), 1.97 (m, 2H), 1.87 (s, 3H), 1.70 (m, 2H), 1.65 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H), 1.57 (s, 3H), 1.49 (s, 3H), 1.35 (m, 1H), 1.29 (s, 3H), 1.08 (s, 3H).

Example 10

Compound 4.1 in Table 1

To a compound of acetylated-4-O-D-allosylbenzoic acid 20 g (42.8 mmol) was added fuming nitric acid 16 ml. The mixture was stirred at −20° C., for 1 h. The reaction solution was added ice water 60 mL. The crude was separated by silica gel column chromatography to give compound 4.1, IR (KBr, cm⁻¹): 3436, 2926, 1753, 1617, 1541, 1701, 1617, 1541, 1500, 1428, 1373, 1231, 1168, 1086, 1066, 1048, 951, 917, 829, 769.

Example 11

Compound 4.2 in Table 1

To a compound of 4.1, 6 g (11.7 mmol) in methanol 30 ml was added H₂. The mixture was stirred at rt for 2 h. The reaction solution was distilled under reduced pressure and the crude was separated by silica gel column chromatography to give compound 4.2, IR (KBr, cm⁻¹): 3476, 3382, 2963, 1751, 1719, 1621, 1599, 1516, 1449, 1374, 1227, 1155, 1091, 1047, 951, 911, 887, 770, 646.

Example 12

Compound 4.3 in Table 1

To a mixture of compound of 4.2, 4.0 g (8.4 mmol) and pyridine 2 ml in methanol 30 ml and THF15 ml was added acetic anhydride 2 ml. The mixture was stirred at rt for 4 h. The ice water was added the reaction solution. The crude was separated by silica gel column chromatography to give compound 4.3, IR (KBr, cm⁻¹): 3391, 2963, 1757, 1714, 1660, 1599, 1544, 1484, 1442, 1375, 1250, 1227, 1078, 1044, 952, 911, 836, 805, 770, 645.

Example 13

Compound 4.4 in Table 1

To a mixture of compound of 4.3, 4.0 g (7.6 mmol), thionyl chloride 0.81 ml, pyridine 0.606 ml, DMAP 0.57 g and triethylamine 1.3 ml in CH₂Cl₂20 ml was added gamboge methyl 3 g. The mixture was stirred at rt for 0.5 h. The reaction solution was distilled under reduced pressure and the aqueous phase was extracted three times with ethyl acetate. The crude was separated by silica gel column chromatography to give compound 4.4, IR (KBr, cm⁻¹): 3435, 2964, 2928, 2847, 1751, 1709, 1663, 1632, 1606, 1537, 1501, 1458, 1431, 1384, 1321, 1226, 1187, 1137, 1091, 1046, 952, 909, 756, 599.

Example 14

Compound 4 in Table 1

To a compound 4.4 2.31 g (2 mmol) was added methanol 30 ml. The mixture was refluxed for 8 h. The reaction solution was distilled under reduced pressure and the crude was separated by silica gel column chromatography to give compound 4, IR (KBr, cm⁻¹): 3429, 2925, 2848, 1740, 1709, 1655, 1633, 1605, 1539, 1458, 1431, 1384, 1262, 1188, 1138, 1046, 805, 755, 502. ¹H NMR (CDCl₃) δ 8.86 (s, 1H), 8.56 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.42 (d, J=10.8 Hz, 1H), 6.00 (t, J=6.0 Hz, 1H), 5.58 (d, J=9.6 Hz, 1H), 5.21 (d, J=7.2 Hz, 1H), 5.07 (m 1H), 5.02 (m, 1H), 4.07 (m, 1H), 3.80˜3.58 (m, 5H), 3.49 (s, 3H), 3.34 (m, 2H), 2.98˜2.70 (m, 2H), 2.64 (m, 2H), 2.47 (d, J=8.4 Hz, 1H), 2.20 (m, 1H), 2.12 (s, 3H), 2.12 (m, 2H), 1.75 (s, 3H), 1.74 (m, 2H), 1.68 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H), 1.54 (s, 3H), 1.44 (s, 3H), 1.29 (m, 1H), 1.26 (s, 3H), 1.22 (s, 3H).

Example 15

Compound 5 in Table 1

To a compound of methyl-6-(4-oxo-D-glucosyl)benzoyl gambogate 2 g (2.15 mmol) in 20 ml acetone, was added p-toluenesulfonic acid 0.37 g (2.15 mmol). The mixture was stirred at rt, for 12 h. The reaction solution was distilled under reduced pressure and the crude was separated by silica gel column chromatography to give compound 5, IR (KBr, cm⁻¹): 3410, 2957, 2924, 2854, 1738, 1716, 1663, 1606, 1515, 1463, 1384, 1322, 1258, 1110, 1043, 849, 690, 606; ¹H NMR (CDCl₃) δ 8.00 (d, J=8.4 Hz, 2H), 7.41 (d, J=6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 6.37 (d, J=10.2 Hz, 1H), 5.94 (t, J=6.0 Hz, 1H), 5.58 (d, J=10.2 Hz, 1H), 5.11 (m, 1H), 5.05 (m, 1H), 3.70 (m, 1H), 3.52 (s, 3H), 3.42 (m, 2H), 3.28 (m, 1H), 3.25 (m, 1H), 3.00 (m, 2H), 2.53 (d, J=9.0 Hz, 1H), 2.29 (m, 1H), 2.04 (m, 2H), 1.81 (s, 3H), 1.79 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H), 1.71 (s, 3H), 1.68 (s, 3H), 1.67 (s, 3H), 1.66 (s, 3H), 1.60 (br, 4H), 1.58 (s, 3H), 1.56 (s, 3H), 1.39 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H).

Example 16

Compound 6.1 in Table 1

To a mixture of compound BOC-L-alanine 18.90 g (0.1 mol) and DMAP 6.10 g (0.05 mol), in THF 200 ml, was added N-methyl-naphthalene methylamine 20.50 g (0.12 mol). The mixture was stirred at room temperature 8 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 6.1, IR (KBr, cm⁻¹): 3426, 2978, 2931, 1709, 1646, 1599, 1511, 1487, 1457, 1414, 1385, 1367, 1250, 1167, 1087, 1051, 1020, 866, 793, 778.

Example 17

Compound 6.2 in Table 1

To a mixture of compound 6.1, 17.10 g (50 mmol), DMAP 3.05 g (25 mmol) and L-alanine-N-methyl naphthalene formamide 55 mmol in THF 100 ml was add gambogic acid 31.4 g (50 mmol). The mixture was stirred at room temperature 6 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 6.2, IR (KBr, cm⁻¹): 3429, 2963, 2925, 2856, 1740, 1639, 1605, 1575, 1508, 1461, 1432, 1384, 1321, 1244, 1172, 1100, 1082, 1043, 908, 850, 793, 760, 688.

Example 18

Compound 6.3 in Table 1

To a mixture of compound 6.2, 21.73 g (25 mmol), DMAP 1.59 g (13 mmol), triethylamine 7 ml in CH₂Cl₂20 ml was add acetylated-4-O-D-allosylbenzoic chloride 7.96 g (25 mmol), gambogic acid 31.4 g (50 mmol). The mixture was stirred at rt for 1 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 6.3, IR (KBr, cm⁻¹): 3450, 2965, 2926, 2856, 1750, 1662, 1639, 1605, 1575, 1509, 1482, 1462, 1374, 1321, 1300, 1175, 1142, 1090, 1045, 949, 910, 852, 760, 687, 600.

Example 19

Compound 6 in Table 1

To a compound 6.3, 13.25 g (10 mmol) was added methanol 100 ml. The mixture was refluxed for 8 h. The reaction solution was distilled under reduced pressure and the crude was separated by silica gel column chromatography to give compound 6, IR (KBr, cm⁻¹): 3445, 2921, 2851, 1747, 1682, 1631, 1604, 1508, 1460, 1374, 1225, 1166, 1092, 1047, 909, 793, 780, 576. ¹H NMR (CDCl₃) δ 8.10˜6.95 (m, 13H), 6.34 (t, J=6.0 Hz, 1H), 5.50 (d, J=10.2 Hz, 1H), 5.31 (m, 1H), 5.23 (m, 1H), 5.08 (m, 1H), 4.98 (m, 1H), 4.78 (m, 2H), 4.59˜4.16 (m, 2H), 3.90-3.40 (br, 4H), 3.33 (m, 2H), 2.92 (m, 3H), 2.43 (d, J=9.0 Hz, 1H), 2.40-2.00 (br, 4H), 1.98 (m, 2H), 1.76 (s, 3H), 1.74 (m, 2H), 1.69 (s, 3H), 1.64 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.39 (m, 1H), 1.27 (s, 3H), 1.19 (s, 3H).

Example 20

Compound 7 in Table 1

To a mixture of malononitrile 132 mg, triethylamine 2 ml in ethanol 10 ml was added methylgambogate 642 mg. The mixture was stirred at rt for 2 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 7, IR (KBr, cm⁻¹): 3434, 3290, 2974, 2928 2880, 2214, 1714, 1646, 1629, 1584, 1454, 1440, 1374, 1255, 1177, 1142, 1126, 1028, 956, 907. ¹H NMR (CDCl₃) δ 11.63 (s, 1H), 6.68 (s, 1H), 6.66 (d, J=10.2 Hz, 1H), 6.22 (m, 1H), 5.49 (d, J=10.2 Hz, 1H), 5.09 (m, 1H), 5.00 (m, 1H), 4.13 (m, 2H), 3.78 (s, 1H), 3.77 (s, 3H), 3.65 (m, 1H), 3.41 (m, 1H), 3.27 (m, 1H), 3.13 (m, 1H), 2.72 (d, J=5.4 Hz, 1H), 2.44 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.69 (s, 3H), 1.67 (br, 3H), 1.63 (br, 3H), 1.56 (m, 3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.38 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

Example 21

Compound 8 in Table 1

To a mixture of methyl gambogate 1.28 g (2 mmol) and triethylamine 5 ml in ethanol 25 ml was added malononitrile 160 mg. The mixture was stirred at rt for 5 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 8, IR (KBr, cm⁻¹): 3427, 2978, 2933, 2880, 2193, 1679, 1624, 1444, 1397, 1368, 1304, 1230, 1217, 1175, 1111, 1096, 1059, 965. ¹H NMR (CDCl₃) δ 11.72 (s, 1H), 6.66 (d, J=10.2 Hz, 1H), 5.47 (d, J=10.2 Hz, 1H), 5.15 (m, 2H), 5.10 (m, 2H), 4.23 (m, 2H), 3.41 (s, 3H), 3.22 (m, 2H), 3.08 (m, 1H), 2.86 (d, J=2.4 Hz, 1H), 2.49 (m, 1H), 2.39 (br, 1H), 2.23 (m, 2H), 2.07 (br, 3H), 1.73 (s, 3H), 1.66 (m, 8H), 1.61 (s, 2H), 1.56 (s, 3H), 1.41 (s, 3H), 1.39 (s, 6H), 1.22 (d, 3H).

Example 22

Compound 9 in Table 1

To a mixture of methyl gambogate 1.284 g (2 mmol) and triethylamine 1.1 g in ethanol 20 ml was added 2-aminoimidazole 320 mg (3.9 mmol). The mixture was stirred at rt for 7 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 9, IR (KBr, cm⁻¹): 3445, 2968, 2926, 1728, 1646, 1626, 1584, 1553, 1455, 1383, 1334, 1297, 1260, 1216, 1172, 1125, 1060, 1034. ¹H NMR (CDCl₃) δ 11.75 (s, 1H), 6.65 (d, J=10.2 Hz, 1H), 6.60 (m, 2H), 5.45 (d, J=10.2 Hz, 1H), 5.11 (m, 3H), 4.76 (m, 1H), 4.08 (m, 1H), 3.69 (m, 1H), 3.46 (s, 1H), 3.42 (s, 3H), 3.25 (m, 1H), 3.16 (m, 2H), 2.35 (m, 3H), 2.08 (m, 5H), 1.77 (m, 1H), 1.71 (s, 1H), 1.66 (s, 3H), 1.62 (s, 3H), 1.56 (s, 3H), 1.44 (m, 4H), 1.41 (s, 3H), 1.39 (br, 2H), 1.37 (m, 3H).

Example 23

Compound 10 in Table 1

To a mixture of methyl gambogate 1.284 g (2 mmol) and triethylamine 1.1 g in ethanol 20 ml was added 2-aminobenzimidazole 320 mg (2.4 mmol). The mixture was stirred at rt for 10 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 10, IR (KBr, cm⁻¹): 3459, 2966, 2926, 1727, 1625, 1584, 1550, 1445, 1397, 1383, 1329, 1299, 1285, 1262, 1235, 1170, 1125, 1093, 1063, 1035, 1007, 961, 920, 820, 740, 603, 547. ¹H NMR (CDCl₃) δ 11.81 (s, 1H), 7.30 (m, 2H), 7.04 (m, 2H), 6.65 (d, J=10.2 Hz, 1H), 5.44 (d, J=10.2 Hz, 1H), 5.11 (m, 2H), 4.90 (m, 1H), 3.37 (m, 1H), 3.20 (m, 1H), 3.08 (s, 3H), 2.65˜3.0 (br, 8H), 2.40 (m, 1H), 2.09 (br, 2H), 1.98 (m, 1H), 1.67 (s, 3H), 1.66 (s, 3H), 1.60 (s, 3H), 1.59 (m, 3H), 1.56 (s, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H).

Example 24

Compound 11 in Table 1

To a mixture of methyl gambogate 1.284 g (2 mmol) and DMAP 250 mg in THF 20 ml and DMF 5 ml, was added piperazine acid 740 mg (5.1 mmol). The mixture was stirred at rt for 11 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 11, IR (KBr, cm⁻¹): 3435, 2962, 2925, 2855, 2688, 2454, 2347, 1767, 1737, 1713, 1658, 1575, 1462, 1432, 1384, 1321, 1227, 1202, 1176, 1136, 1047, 978, 877, 804, 758; ¹H NMR (CDCl₃) δ 7.38 (d, J=6.6 Hz, 1H), 6.50 (d, J=10.2 Hz, 1H), 6.00 (br, 1H), 5.61 (m, J=10.2 Hz, 1H), 5.05 (m, 2H), 3.86 (br, 2H), 3.41 (m, 4H), 3.22 (br, 1H), 3.10 (br, 2H), 2.97 (br, 1H), 2.65˜3.0 (br, 8H), 2.60 (m, 3H), 2.53 (m, 1H), 2.30 (m, 2H), 2.02 (m, 3H), 1.75˜1.90 (m, 4H), 1.70˜1.60 (m, 12H), 1.56 (m, 3H), 1.47 (s, 3H), 1.36 (m, 2H), 1.31 (s, 3H).

Example 25

Compound 12 in Table 1

To a mixture of methyl gambogate 642 mg (1 mmol), triethylamine 0.5 ml, DMSO 20 ml, DMAP 250 mg in THF 20 ml and DMF 5 ml was added ciprofloxacin 440 mg (1.3 mmol). The mixture was stirred at rt for 20 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 12, IR (KBr, cm⁻¹): 3451, 2970, 2925, 2853, 1737, 1627, 1584, 1548, 1505, 1454, 1383, 1325, 1302, 1257, 1216, 1176, 1124, 1006, 893, 835, 807, 747; ¹H NMR (CDCl₃) δ 15.05 (s, 1H, —COOH), δ 11.98 (s, 1H, —OH), δ 8.77 (s, 1H), δ 8.00 (d, 1H, J=13.2 Hz), 7.32 (d, 1H, J=7.2 Hz), 6.67 (d, 1H, J=10.2 Hz, 1H, 4-H), 6.64 (t, 1H, J=6.6 Hz), 5.47 (d, 1H, J=10.2 Hz, 1H, 3-H), 5.10 (m, 1H), 5.01 (m, 1H), 3.59 (s, 1H, COOCH 3), 3.53 (m, 1H), 3.42 (m, 1H), 3.30 (m, 4H), 3.18 (m, 4H), 2.84 (br, 3H), 2.67 (m, 2H), 2.56 (d, 1H, J=8.4 Hz), 2.09 (br, 2H), 2.03 (m, 2H), 1.95 (s, 3H), 1.70 (m, 4H), 1.68 (m, 9H), 1.57 (s, 3H), 1.41 (m, 2H), 1.36 (s, 6H), 1.10 (m, 2H), 1.17 (s, 3H).

Example 26

Compound 13 in Table 1

To a mixture of methyl-10-morpholine gambogate 1.46 g and DMAP 250 mg was added chloroacetic acid 500 mg (5.2 mmol). The mixture was stirred at rt for 4 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 13, IR (KBr, cm⁻¹): 3436, 2965, 2925, 2855, 1791, 1739, 1714, 1678, 1642, 1605, 1573, 1460, 1384, 1320, 1276, 1234, 1176, 1133, 1050, 1021, 887, 842, 808, 744, 570.

Example 27

Compound 14.1 in Table 1

To a compound of methyl-6-O-(2-chloroacetyl) gambogate 1.440 mg (2 mmol) in THF 40 ml was added palladium acetate 50 mg. The mixture was stirred at rt for 7 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 14.1, IR (KBr, cm⁻¹): 3448, 2971, 2925, 1737, 1715, 1632, 1594, 1436, 1401, 1382, 1175, 1135.

Example 28

Compound 14 in Table 1

To a compound 14.1 600 mg (1.2 mmol) and triethylamine 0.8 g in ethanol 20 ml was added 2-aminoimidazole 110 mg (1.3 mmol). The mixture was stirred at rt for 7 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 14, ¹H NMR (CDCl₃) δ 6.65 (d, J=10.2 Hz, 1H), 6.60 (m, 2H), 5.45 (d, J=10.2 Hz, 1H), 5.11 (m, 3H), 4.76 (m, 1H), 4.08 (m, 1H), 3.69 (m, 1H), 3.42 (s, 3H), 3.25 (m, 1H), 3.16 (m, 2H), 2.91 (s, 2H), 2.35 (m, 3H), 2.08 (m, 5H), 1.77 (m, 1H), 1.71 (s, 1H), 1.66 (s, 3H), 1.62 (s, 3H), 1.56 (s, 3H), 1.44 (m, 4H), 1.41 (s, 3H), 1.39 (br, 2H), 1.37 (m, 3H).

Example 29

Compound 15.1 in Table 1

To a mixture of methylgambogate 321 mg (0.5 mmol), potassium carbonate 138 mg (1 mmol) and sodium iodide 78 mg (0.52 mmol) in DMF 10 ml was added 1,2-dibromomethane 90 mg (0.52 mmol). The mixture was stirred at rt for 3 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 15.1.

Example 30

Compound 15 in Table 1

To a compound 15.1 642 mg (1 mmol) in THF 10 ml was added aminotriazole 100 mg (1.2 mmol). The mixture was stirred at rt for 12 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 15, ¹HNMR (CDCl³) δ 7.27 (s, 1H), 6.65 (d, J=5.1 Hz, 1H), 6.15 (m, 2H), 5.47 (d, J=5.1 Hz, 1H), 5.20 (s, 1H), 5.10 (m, 2H), 4.36 (m, 2H), 3.80 (s, 3H), 3.34 (m, 1H), 3.18 (m, 1H), 3.09 (m, 1H), 2.85 (s, 1H), 2.54 (t, J=2.1 Hz, 1H), 2.41 (d, J=4.8 Hz, 1H), 2.35 (q, J=7.8 Hz, 1H), 2.26 (q, J=6.9 Hz, 1H), 2.08 (m, 3H), 1.76 (m, 6H), 1.72 (s, 3H), 1.66 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H), 0.85 (s, 3H).

Example 31

Compound 16 in Table 1

To a mixture of methyl-6-(2-bromoethyl) gambogate 224 mg (0.3 mmol), potassium carbonate 82.8 mg (0.6 mmol) in DMF 10 ml was added ethanolamine 20 mg (0.33 mmol). The mixture was stirred at rt for 8 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 16, IR (KBr, cm-1): 3410, 2957, 2924, 2854, 1738, 1716, 1663, 1606, 1515, 1463, 1384, 1322, 1258, 1110, 1043, 849, 690, 606; ¹H NMR (CDCl₃) δ 7.46 (d, J=6.9 Hz, 1H), 6.73 (m, 1H), 5.95 (m, J=7.4 Hz, 1H), 5.67 (d, J=10.2 Hz, 1H), 5.09 (m, 2H), 3.44 (m, 6H), 3.00 (m, 2H), 2.54 (m, 1H), 2.30 (m, 1H), 2.06 (m, 2H), 1.84˜1.75 (br, 5H), 1.74˜1.59 (m, 14H), 1.58 (m, 4H), 1.55 (m, 4H), 1.46 (s, 4H), 1.30 (s, 6H).

Example 32

Compound 17 in Table 1

To a mixture of methyl gambogate 642 mg (1 mmol) in ethanol 10 ml was added aminotriazole 100 mg (1.2 mmol). The mixture was stirred at rt for 12 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 17, IR (KBr, cm⁻¹): 3438, 2921, 1735, 1710, 1629, 1554, 1451, 1383, 1246, 1158, 1021, 789. ¹H NMR (CDCl₃) δ 11.60 (s, 1H), 7.27 (s, 1H), 6.65 (d, J=5.1 Hz, 1H), 5.47 (d, J=5.1 Hz, 1H), 5.20 (s, 1H), 5.10 (m, 2H), 4.36 (m, 2H), 3.80 (s, 3H), 3.34 (m, 1H), 3.18 (m, 1H), 3.09 (m, 1H), 2.85 (s, 1H), 2.54 (t, J=2.1 Hz, 1H), 2.41 (d, J=4.8 Hz, 1H), 2.35 (q, J=7.8 Hz, 1H), 2.26 (q, J=6.9 Hz, 1H), 2.08 (m, 3H), 1.76 (m, 6H), 1.72 (s, 3H), 1.66 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H), 0.85 (s, 3H).

Example 33

Compound 18 in Table 1

To a mixture of methyl gambogate 642 mg (1 mmol) in ethanol 10 ml was added aminotriazole 100 mg (1.2 mmol). The mixture was refluxed for 16 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 18, IR (KBr, cm⁻¹): 3437, 2925, 1737, 1628, 1554, 1458, 1383, 1173, 1126, 1025, 752; ¹HNMR (CDCl₃) δ 12.79 (s, 1H), 7.26 (s, 1H), 6.67 (d, J=10.5 Hz, 1H), 6.37 (m, 1H), 5.45 (d, J=10.2 Hz, 1H), 5.10 (m, 2H), 3.65 (s, 3H), 3.50 (m, 2H), 3.26 (d, J=6.6 Hz, 2H), 2.62 (d, J=7.5 Hz, 2H), 2.53 (d, J=9.3 Hz, 1H), 2.34 (m, 1H), 2.04 (m, 2H), 1.74 (s, 3H), 1.71 (s, 3H), 1.65 (m, 7H), 1.56 (m, 5H), 1.43 (s, 3H), 1.37 (s, 3H), 1.30 (s, 3H).

Example 34

Compound 19.1 in Table 1

To a mixture of methyl gambogate 642 mg (1 mmol) in ethanol 10 ml was added malononitrile 330 mg (5 mmol). The mixture was refluxed for 3 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 19.1.

Example 35

Compound 19 in Table 1

To a mixture of methyl-9,10-dihydro-O-adiponitrile gambogate 694 mg (1 mmol) and potassium carbonate 690 mg (5 mmol) in ethanol 10 ml was added hydroxylamine hydrochloride 350 mg (5 mmol). The mixture was refluxed for 18 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 19, IR (KBr, cm⁻¹): 3435, 2976, 2938, 2739, 2678, 2530, 2492, 1647, 1476, 1398, 1383, 1172, 1143, 1073, 1036, 850, 806 ¹H NMR (CDCl₃) δ 12.76 (s, 1H), 7.49 (m, 1H), 5.90 (m, 1H), 5.10 (m, 1H), 4.59 (s, 1H), 4.28 (m, 1H), 3.56 (m, 1H), 3.46 (m, 4H), 3.43˜3.20 (m, 2H), 2.96 (m, 2H), 2.54˜2.21 (m, 4H), 1.93 (m, 5H), 1.84 (m, 2H), 1.77˜1.71 (m, 7H), 1.66˜1.64 (m, 8H), 1.58˜1.52 (m, 2H), 1.41˜1.31 (m, 6H), 1.28˜1.25 (m, 4H).

Example 36

Compound 20 in Table 1

To a mixture of methyl gambogate 694 mg (1 mmol), methylamine hydrochloride 135 mg (2 mmol) and triethylamine 404 mg (4 mmol) in DMF 10 ml was added indanedione 176 mg (1.2 mmol). The mixture was stirred at rt for 12 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 20, IR (KBr, cm⁻¹): 3434, 2924, 2853, 1721, 1620, 1595, 1428, 1351, 1253, 1138, 1072, 991, 736, 681 ¹H NMR (CDCl₃) δ 11.81 (s, 1H), 7.94 (m, 2H), 7.87 (m, 2H), 6.62 (m, 2H), 5.45 (d, J=10.2 Hz, 1H), 5.08 (m, 2H), 4.26 (d, J=3.6 Hz, 1H), 3.65 (s, 3H), 3.37˜3.23 (m, 6H), 2.95 (m, 1H), 2.69 (d, J=11.4 Hz, 1H), 2.58 (d, J=8.7 Hz, 1H), 2.17˜2.05 (m, 4H), 1.95 (s, 3H), 1.76 (s, 3H), 1.66 (m, 6H), 1.57 (m, 5H), 1.39 (s, 3H), 1.38 (s, 3H), 1.17 (s, 3H).

Example 37

Compound 21 in Table 1

To a mixture of methyl gambogate 694 mg (1 mmol) and triethylamine 404 mg (4 mmol) in DMF 10 ml was added o-amino thiophenol 150 mg (1.2 mmol). The mixture was stirred at rt for 20 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 21, IR (KBr, cm⁻¹): 3460, 3370, 2970, 2924, 2853, 1738, 1713, 1628, 1479, 1454, 1397, 1367, 1309, 1220, 1174, 1045, 987, 955; ¹H NMR (CDCl₃) δ 11.80 (s, 1H), 7.53 (d, J=3.9 Hz, 1H), 7.23 (t, J=3.6 Hz, 1H), 7.03 (m, 1H), 6.86 (t, J=3.6 Hz, 1H), 6.66 (d, J=5.1 Hz, 1H), 6.63 (m, 1H), 5.46 (d, J=5.1 Hz, 1H), 5.07 (m, 2H), 4.33 (s, 1H), 3.73 (s, 3H), 3.44˜3.15 (m, 5H), 2.51 (d, J=4.2 Hz, 1H), 2.48 (s, 1H), 2.09˜1.94 (m, 3H), 1.74 (s, 3H), 1.68˜1.62 (m, 9H), 1.57 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H), 1.27 (s, 3H), 1.11 (s, 3H).

Example 38

Compound 22 in Table 1

To a mixture of methyl gambogate 694 mg (1 mmol) and diamine 72 mg (1.2 mmol) in DMF 10 ml was added indanedione 176 mg (1.2 mmol). The mixture was stirred at rt for 12 h. The reaction solution was distilled under reduced pressure. The crude was separated by silica gel column chromatography to give compound 22, IR (KBr, cm⁻¹): 3431, 2925, 1739, 1709, 1626, 1523, 1453, 1383, 1321, 1253, 1217, 1175, 1125, 907, 840, 754, 620. 1H NMR (CDCl₃) δ 11.92 (s, 1H), 7.58 (m, 2H), 6.90 (m, 2H), 6.57 (d, J=5.1 Hz, 1H), 6.49 (m, 1H), 5.38 (d, J=5.1 Hz, 1H), 5.22 (d, J=3.6 Hz, 1H), 5.02˜4.92 (m, 3H), 4.25˜4.18 (m, 4H), 3.78 (m, 2H), 3.59 (m, 5H), 3.21˜3.18 (m, 4H), 2.75 (m, 2H), 2.40 (m, 1H), 2.00 (m, 2H), 1.85 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H), 1.50 (s, 3H), 1.28 (s, 3H), 1.03 (s, 3H).

TABLE 1

Embodiment 1-441

Ex-
am-			M.
ple	Chemical Structure	Formula	Weight

1		C₅₃H₆₃NO₁₅	954.07

1.1		C₄₂H₅₁O₈	713.86

1.2		C₆₃H₇₃NO₂₀	1164.25

2		C₆₁H₆₅NO₁₅	1052.17

2.1		C₄₈H₅₁NO₈	769.92

2.2		C₆₉H₇₅NO₁₉	1222.33

3		C₅₃H₆₃NO₁₅	954.07

3.1		C₂₃H₂₉NO₁₂	511.48

3.2		C₆₁H₇₁NO₁₉	1122.21

4		C₅₄H₆₃NO₁₆	982.08

4.1		C₂₁H₂₃NO₁₄	513.41

4.2		C₂₁H₂₅NO₁₂	483.42

4.3		C₂₃H₂₇NO₁₃	525.46

4.4		C₅₃H₆₀N₂O₈	853.05

5		C₅₅H₆₄NO₁₅	965.09

6		C₆₆H₇₄N₂O₁₅	1135.3

6.1		C₂₀H₂₆N₂O₃	342.43

6.2		C₅₃H₆₀N₂O₈	853.05

6.3		C₇₄H₈₂N₂O₁₉	1303.44

6.4		C₆₆H₇₄N₂O₁₅	1135.3

7		C₄₂H₄₈N₂O₈	708.84

8		C₄₃H₅₁N₃O₇	721.88

9		C₄₂H₄₉N₃O₇	707.85

10		C₄₆H₅₁N₃O₇	757.91

11		C₄₈H₆₀N₂O₁₀	825

12		C₅₆H₆₄FN₃O₁₁	974.12

13		C₄₃H₅₆ClNO₁₀	806.38

14		C₄₄H₄₉N₃O₈	747.88

15		C₄₂H₅₁N₅O₇	737.88

16		C₄₃H₅₅NO₉	729.9

17		C₄₁H₅₀N₄O₈	726.86

18		C₄₁H₄₈N₄O₇	708.84

19		C₄₂H₅₄N₄O₁₀	774.9

19.1		C₄₂H₄₈N₂O₈	708.84

20		C₄₉H₅₃NO₈	783.95

21		C₄₅H₅₁NO₇S	749.95

22		C₅₀H₅₆N₂O₈	812.99

23		C₄₈H₅₉N₃O₁₂	869.99

24		C₄₈H₅₉N₃O₁₂	869.99

25		C₅₁H₆₃N₃O₁₂	910.06

26		C₅₁H₆₃N₃O₁₂	910.06

27		C₅₅H₆₃N₃O₁₄	990.1

28		C₅₅H₆₃N₃O₁₄	990.1

29		C₄₃H₅₁N₃O₇	721.88

30		C₅₀H₆₃N₅O₉	890.07

31		C₄₂H₅₀N₃O₁₀P	787.83

32		C₄₂H₅₂N₃O₁₆P₃	947.79

33		C₅₀H₆₁N₅O₉	876.05

34		C₄₄H₅₀ClN₃O₈	784.34

35		C₄₆H₅₈N₄O₈	794.97

36		C₄₉H₆₃N₅O₇	834.05

37		C₄₉H₆₃N₅O₇	780.95

38		C₄₃H₅₀BrN₃O₇	800.78

39		C₅₈H₆₇N₃O₁₄	1030.16

40		C₄₇H₅₈N₄O₁₂	870.98

41		C₄₇H₅₈N₄O₁₂	870.98

42		C₅₀H₆₂N₄O₁₂	911.05

43		C₅₀H₆₂N₄O₁₂	911.05

44		C₅₄H₆₂N₄O₁₄	991.09

45		C₅₄H₆₂N₄O₁₄	991.09

46		C₄₂H₅₀N₄O₇	722.87

47		C₅₀H₆₂N₆O₉	891.06

48		C₄₁H₄₉N₄O₁₀P	788.82

49		C₄₁H₅₁N₄O₁₆P₃	948.78

50		C₄₉H₆₀N₆O₉	877.04

51		C₄₃H₄₉ClN₄O₈	785.32

52		C₄₅H₅₇N₅O₈	795.96

53		C₄₈H₆₂N₆O₇	835.04

54		C₄₄H₅₅N₅O₈	781.94

55		C₄₃H₄₈N₄O₈	748.86

56		C₄₂H₄₉BrN₄O₇	801.77

57		C₅₇H₆₆N₄O₁₄	1031.15

58		C₄₂H₄₉N₃O₇	707.85

59		C₄₈H₅₉N₃O₁₂	869.99

60		C₄₈H₅₉N₃O₁₂	869.99

61		C₅₁H₆₃N₃O₁₂	910.06

62		C₅₁H₆₃N₃O₁₂	910.06

63		C₅₅H₆₃N₃O₁₄	990.1

64		C₅₅H₆₃N₃O₁₄	990.1

65		C₄₃H₅₁N₃O₇	721.88

66		C₅₁H₆₃N₅O₉	890.07

67		C₄₂H₅₀N₃O₁₀P	787.83

68		C₄₂H₅₂N₃O₁₆P₃	947.79

69		C₅₀H₆₁N₅O₉	876.05

70		C₄₄H₅₀ClN₃O₈	784.34

71		C₄₆H₅₈N₄O₈	794.97

72		C₄₉H₆₃N₅O₇	834.05

73		C₄₅H₅₆N₄O₈	780.95

74		C₄₄H₄₉N₃O₈	747.88

75		C₄₃H₅₀BrN₃O₇	800.78

76		C₅₈H₆₇N₃O₁₄	1030.16

77		C₄₉H₆₁N₃O₁₂	884.02

78		C₄₉H₆₁N₃O₁₂	884.02

79		C₅₂H₆₅N₃O₁₂	924.09

80		C₅₂H₆₅N₃O₁₂	924.09

81		C₅₆H₆₅N₃O₁₄	1004.13

82		C₅₃H₆₅N₃O₁₄	1004.13

83		C₄₄H₅₃N₃O₇	735.91

84		C₅₂H₆₅N₅O₉	904.1

85		C₄₃H₅₂N₃O₁₀P	801.86

86		C₄₄H₅₅N₂O₁₆P₃	960.83

87		C₅₁H₆₃N₅O₉	890.07

88		C₄₅H₅₂ClN₃O₈	798.36

89		C₄₇H₆₀N₄O₈	809

90		C₅₀H₆₅N₅O₇	848.08

91		C₄₆H₅₈N₄O₈	794.97

92		C₄₅H₅₁N₃O₈	761.9

93		C₄₄H₅₂BrN₃O₇	814.8

94		C₅₉H₆₉N₃O₁₄	1044.19

95		C₄₈H₅₈N₂O₁₃	870.98

96		C₄₈H₅₈N₂O₁₃	870.98

97		C₅₁H₆₂N₂O₁₃	911.04

98		C₅₁H₆₂N₂O₁₃	911.04

99		C₅₅H₆₂N₂O₁₅	991.09

100		C₅₅H₆₂N₂O₁₅	991.09

101		C₄₃H₅₀N₂O₈	722.87

102		C₅₁H₆₂N₄O₁₀	891.06

103		C₄₂H₄₉N₂O₁₁P	788.82

104		C₄₂H₅₁N₂O₁₇P₃	948.78

105		C₅₀H₆₀N₄O₁₀	877.03

106		C₄₄H₄₉ClN₂O₉	785.32

107		C₄₆H₅₇N₃O₉	795.96

108		C₄₉H₆₂N₄O₈	835.04

109		C₄₅H₅₅N₃O₉	781.93

110		C₄₄H₄₈N₂O₉	748.86

111		C₄₃H₄₉BrN₂O8	801.76

112		C₅₈H₆₆N₂O₁₅	1031.15

113		C₅₂H₆₁N₃O₁₂	920.05

114		C₅₂H₆₁N₃O₁₂	920.05

115		C₅₅H₆₅N₃O₁₂	960.12

116		C₅₅H₆₅N₃O₁₂	960.12

117		C₅₉H₆₅N₃O₁₄	1040.16

118		C₅₉H₆₅N₃O₁₄	1040.16

119		C₄₇H₅₃N₃O₇	771.94

120		C₅₅H₆₅N₅O₉	940.13

121		C₄₆H₅₂N₃O₁₀P	837.89

122		C₄₆H₅₄N₃O₁₆P₃	997.85

123		C₅₄H₆₃N₅O₉	926.11

124		C₄₈H₅₂ClN₃O₈	834.39

125		C₅₀H₆₀N₄O₈	845.03

126		C₅₃H₆₅N₅O₇	884.11

127		C₄₉H₅₈N₄O₈	831.01

128		C₄₈H₅₁N₃O₈	797.93

129		C₄₇H₅₂BrN₃O₇	850.84

130		C₆₂H₆₉N₃O₁₄	1080.22

131		C₅₁H₆₁NO₁₂S	912.09

132		C₅₁H₆₁NO₁₂S	912.09

133		C₅₄H₆₅NO₁₂S	952.16

134		C₅₄H₆₅NO₁₂S	952.16

135		C₅₈H₆₅NO₁₄S	1032.2

136		C₅₈H₆₅NO₁₄S	1032.2

137		C₄₆H₅₃NO₇S	763.98

138		C₅₄H₆₅N₃O₉S	932.17

139		C₄₅H₅₂NO₁₀PS	829.93

140		C₄₅H₅₄NO₁₆P₃S	989.89

141		C₅₃H₆₃N₃O₉S	918.15

142		C₄₇H₅₂ClNO₈S	826.44

143		C₄₉H₆₀N₂O₈S	837.07

144		C₅₂H₆₅N₃O₇S	876.15

145		C₄₈H₅₈N₂O₈S	823.05

146		C₄₇H₅₁NO₈S	789.97

147		C₄₆H₅₂BrNO₇S	842.88

148		C₆₁H₆₉NO₁₄S	1072.26

149		C₄₈H₅₀O₉	770.91

150		C₅₄H₆₀O₁₄	933.05

151		C₅₄H₆₀O₁₄	933.05

152		C₅₇H₆₄O₁₄	973.11

153		C₅₇H₆₆O₁₄	973.11

154		C₆₁H₆₆O₁₆	1053.15

155		C₆₁H₆₆O₁₆	1053.15

156		C₄₉H₅₂O₉	784.93

157		C₅₇H₆₄N₂O₁₁	953.12

158		C₄₈H₅₁O₁₂P	850.89

159		C₄₈H₅₃O₁₈P₃	1010.84

160		C₅₆H₆₂N₂O₁₁	939.1

161		C₅₀H₅₁ClO₁₀	847.39

162		C₅₂H₅₉NO₁₀	858.03

163		C₅₅H₆₄N₂O₉	897.1

164		C₅₁H₅₇NO₁₀	844

165		C₅₀H₅₀O₁₀	810.93

166		C₄₉H₅₁BrO₉	863.93

167		C₆₄H₆₈O₁₆	1093.22

168		C₄₈H₅₁O₈	769.92

169		C₅₄H₆₁NO₁₃	932.06

170		C₅₄H₆₁NO₁₃	932.06

171		C₅₇H₆₅NO₁₃	972.12

172		C₅₇H₆₅NO₁₃	972.12

173		C₆₁H₆₅NO₁₅	1052.17

174		C₄₉H₅₃NO₈	783.95

175		C₅₇H₆₅N₃O₁₀	952.14

176		C₄₈H₅₂NO₁₁P	849.9

177		C₄₈H₅₄NO₁₇P₃	1009.86

178		C₅₆H₆₃N₃O₁₀	938.11

179		C₅₀H₅₂ClNO₉	846.4

180		C₅₂H₆₀N₂O₉	857.04

181		C₅₅H₆₅N₃O₈	896.12

182		C₅₁H₅₈N₂O₉	843.01

183		C₅₀H₅₁NO₉	809.94

184		C₄₉H₅₂BrNO₈	862.84

185		C₆₄H₆₉NO₁₅	1092.23

186		C₄₇H₆₀N₄O₁₃	889

187		C₄₇H₆₀N₄O₁₃	889

188		C₅₀H₆₄N₄O₁₃	929.06

189		C₅₀H₆₄N₄O₁₃	929.06

190		C₅₄H₆₄N₄O₁₅	1009.1

191		C₅₄H₆₄N₄O₁₅	1009.1

192		C₄₂H₅₂N₄O₈	740.88

193		C₅₀H₆₄N₆O₁₀	909.08

194		C₄₁H₅₁N₄O₁₁P	806.84

195		C₄₁H₅₃N₄O₁₇P₃	966.8

196		C₄₉H₆₂N₆O₁₀	895.05

197		C₄₃H₅₁ClN₄O₉	803.34

198		C₄₆H₆₀N₄O₉	812.99

199		C₄₉H₆₅N₅O₈	852.07

200		C₄₄H₅₇N₅O₉	799.95

201		C₄₄H₅₁N₃O₉	765.89

202		C₄₃H₅₂BrN₃O₈	818.79

203		C₅₈H₆₉N₃O₁₅	1048.18

204		C₄₂H₄₈N₂O₈	708.84

205		C₄₈H₅₈N₂O₁₃	870.98

206		C₄₈H₅₈N₂O₁₃	870.98

207		C₅₁H₆₂N₂O₁₃	911.04

208		C₅₁H₆₂N₂O₁₃	911.04

209		C₅₅H₆₂N₂O₁₅	991.09

210		C₅₅H₆₂N₂O₁₅	991.09

211		C₄₃H₅₀N₂O₈	722.87

212		C₅₁H₆₂N₄O₁₀	891.06

213		C₄₂H₄₉N₂O₁₁P	788.82

214		C₄₂H₅₁N₂O₁₇P₃	948.78

215		C₅₀H₆₀N₄O₁₀	877.03

216		C₄₄H₄₉ClN₂O₉	785.32

217		C₄₆H₅₇N₃O₉	795.96

218		C₄₉H₆₂N₄O₈	835.04

219		C₄₅H₅₅N₃O₉	781.93

220		C₄₄H₄₈N₂O₉	748.86

221		C₄₃H₄₉BrN₂O₈	801.76

222		C₅₈H₆₆N₂O₁₅	1031.15

223		C₄₃H₅₁N₃O₇	721.88

224		C₄₈H₆₄N₄O₁₅	937.04

225		C₄₉H₆₆N₄O₁₄	935.07

226		C₅₁H₆₈N₄O₁₅	977.1

227		C₅₁H₆₈N₄O₁₅	977.1

228		C₅₅H₆₈N₄O₁₇	1057.15

229		C₅₅H₆₈N₄O₁₇	1057.15

230		C₄₃H₅₆N₄O₁₀	788.93

231		C₅₁H₆₈N₂O₁₂	957.12

232		C₄₂H₅₅N₄O₁₃P	854.88

233		C₄₂H₅₇N₄O₁₉P₃	1014.84

234		C₅₀H₆₆N₆O₁₂	943.09

235		C₄₄H₅₅ClN₄O₁₁	851.38

236		C₄₆H₆₃N₅O₁₁	862.02

237		C₄₉H₆₈N₆O₁₀	901.1

238		C₄₅H₆₁N₅O₁₁	847.99

239		C₄₄H₅₄N₄O₁₁	814.92

240		C₄₃H₅₅BrN₄O₁₀	867.82

241		C₅₈H₇₂N₄O₁₇	1097.21

242		C₄₃H₅₇N₅O₉	787.94

243		C₄₁H₄₈N₄O₇	708.84

244		C₄₇H₅₈N₄O₁₂	870.98

245		C₄₇H₅₈N₄O₁₂	870.98

246		C₅₀H₆₂N₄O₁₂	911.05

247		C₅₀H₆₂N₄O₁₂	911.05

248		C₅₄H₆₂N₄O₁₄	991.09

249		C₅₄H₆₂N₄O₁₄	991.09

250		C₄₂H₅₀N₄O₇	722.87

251		C₅₀H₆₂N₆O₉	891.06

252		C₄₁H₄₉N₄O₁₀P	788.82

253		C₄₁H₅₁N₄O₁₆P₃	948.78

254		C₄₉H₆₀N₆O₉	877.04

255		C₄₃H₄₉ClN₄O₈	785.32

256		C₄₅H₅₇N₅O₈	795.96

257		C₄₈H₆₂N₆O₇	835.04

258		C₄₄H₅₅N₅O₈	781.94

259		C₄₄H₅₀N₄O₈	762.89

260		C₄₂H₄₉BrN₄O₇	801.77

261		C₅₇H₆₆N₄O₁₄	1031.15

262		C₆₂H₇₄FN₃O₁₆	1136.26

263		C₆₂H₇₄FN₃O₁₆	1136.26

264		C₅₇H₆₆FN₃O₁₁	988.15

265		C₅₅H₆₆N₂O₁₃	975.13

266		C₅₅H₆₆N₂O₁₃	975.13

267		C₅₉H₇₀N₂O₁₃	1015.19

268		C₅₉H₇₀N₂O₁₃	1015.19

269		C₆₃H₇₀N₂O₁₅	1095.23

270		C₆₃H₇₀N₂O₁₅	1095.23

271		C₅₁H₅₈N₂O₈	827.01

272		C₅₉H₇₀N₄O₁₀	995.21

273		C₅₀H₅₇N₂O₁₁P	892.97

274		C₅₀H₅₉N₂O₁₇P₃	1052.93

275		C₅₈H₆₈N₄O₁₀	981.18

276		C₅₂H₅₇ClN₂O₉	889.47

277		C₅₄H₆₅N₃O₉	900.11

278		C₅₇H₇₀N₄O₈	939.19

279		C₅₃H₆₃N₃O₉	886.08

280		C₅₂H₅₆N₂O₉	853.01

281		C₅₃H₅₇BrN₂O₈	905.91

282		C₆₆H₇₄N₂O₁₅	1135.3

283		C₅₂H₆₉NO₁₄	932.1

284		C₅₂H₆₉NO₁₄	932.1

285		C₅₂H₆₉N₃O₁₁	912.12

286		C₅₁H₆₇N₃O₁₁	898.09

287		C₄₇H₆₄N₂O₁₀	817.02

288		C₅₀H₆₉N₃O₉	856.1

289		C₄₆H₆₂N₂O₁₀	802.99

290		C₄₅H₅₅NO₁₀	769.92

291		C₄₄H₅₆BrNO₉	822.82

292		C₅₉H₇₃NO₁₆	1052.21

293		C₄₄H₅₈N₂O₈	742.94

294		C₅₃H₇₂N₂O₁₃	945.14

295		C₅₃H₇₂N₂O₁₃	945.14

296		C₅₃H₇₂N₄O₁₀	925.16

297		C₅₂H₇₀N₄O₁₀	911.13

298		C₄₆H₅₉ClN₂O₉	819.42

299		C₄₈H₆₇N₃O₉	830.06

300		C₅₁H₇₂N₄O₈	869.14

301		C₄₇H₆₅N₃O₉	816.03

302		C₄₆H₅₈N₂O₉	782.96

303		C₄₅H₅₉BrN₂O₈	835.86

304		C₆₀H₇₆N₂O₁₅	1065.25

305		C₄₅H₆₁N₃O₇	755.98

306		C₅₀H₅₆N₂O₈	812.99

307		C₅₆H₆₆N₂O₁₃	975.13

308		C₅₆H₆₆N₂O₁₃	975.13

309		C₆₀H₇₂N₂O₁₂	1013.22

310		C₆₀H₇₂N₂O₁₂	1013.22

311		C₆₃H₇₀N₂O₁₅	1095.23

312		C₆₃H₇₀N₂O₁₅	1095.23

313		C₅₁H₅₈N₂O₈	827.01

314		C₅₉H₇₀N₂O₁₀	995.21

315		C₅₀H₅₇N₂O₁₁P	892.97

316		C₅₀H₅₉N₂O₁₇P₃	1052.93

317		C₅₈H₆₈N₄O₁₀	981.18

318		C₅₂H₅₇ClN₂O₉	889.47

319		C₅₅H₆₆N₂O₉	899.12

320		C₅₈H₇₁N₃O₈	938.2

321		C₅₄H₆₄N₂O₉	885.09

322		C₅₂H₅₆N₂O₉	853.01

323		C₅₁H₅₇BrN₂O₈	905.91

324		C₆₆H₇₄N₂O₁₅	1135.3

325		C₄₂H₅₁N₅O₇	737.88

326		C₄₈H₆₁N₅O₁₂	900.02

327		C₄₈H₆₁N₅O₁₂	900.02

328		C₅₁H₆₅N₅O₁₂	940.09

329		C₅₁H₆₅N₅O₁₂	940.09

330		C₅₅H₆₅N₅O₁₄	1020.13

331		C₅₅H₆₅N₅O₁₄	1020.13

332		C₄₃H₅₃N₅O₇	751.91

333		C₅₁H₆₅N₇O₉	920.1

334		C₄₂H₅₂N₅O₁₀P	817.86

335		C₄₂H₅₄N₅O₁₆P₃	977.82

336		C₅₀H₆₃N₇O₉	906.08

337		C₄₄H₅₂ClN₅O₈	814.37

338		C₄₆H₆₀N₆O₈	825

339		C₄₉H₆₅N₇O₇	864.08

340		C₄₅H₅₈N₆O₈	810.98

341		C₄₄H₅₁N₅O₈	777.9

342		C₄₃H₅₂BrN₅O₇	830.81

343		C₅₈H₆₉N₅O₁₄	1060.19

344		C₄₃H₅₂N₄O₇	736.9

345		C₄₉H₆₂N₄O₁₂	899.04

346		C₄₉H₆₂N₄O₁₂	899.04

347		C₅₂H₆₆N₄O₁₂	939.1

348		C₅₂H₆₆N₄O₁₂	939.1

349		C₅₆H₆₆N₄O₁₄	1019.14

350		C₅₆H₆₆N₄O₁₄	1019.14

351		C₄₄H₅₄N₄O₇	750.92

352		C₅₂H₆₆N₆O₉	919.12

353		C₄₃H₅₃N₄O₁₀P	816.88

354		C₄₃H₅₅N₄O₁₆P₃	976.84

355		C₅₁H₆₄N₆O₉	905.09

356		C₄₅H₅₃ClN₄O₈	813.38

357		C₄₇H₆₁N₅O₈	824.02

358		C₅₀H₆₆N₆O₇	863.1

359		C₄₆H₅₉N₅O₈	809.99

360		C₄₅H₅₂N₄O₈	776.92

361		C₄₄H₅₃BrN₄O₇	829.82

362		C₅₉H₇₀N₄O₇	1059.21

363		C₄₇H₅₄N₄O₇	786.95

364		C₅₃H₆₄N₄O₁₂	949.09

365		C₅₃H₆₄N₄O₁₂	949.09

366		C₅₆H₆₈N₄O₁₂	989.16

367		C₅₆H₆₈N₄O₁₂	989.16

368		C₆₀H₆₈N₄O₁₄	1069.2

369		C₆₀H₆₈N₄O₁₄	1069.2

370		C₄₈H₅₆N₄O₇	800.98

371		C₅₆H₆₈N₆O₉	969.17

372		C₄₇H₅₅N₄O₁₀P	866.93

373		C₄₇H₅₇N₄O₁₆P₃	1026.89

374		C₅₅H₆₆N₆O₉	955.15

375		C₄₉H₅₅ClN₄O₈	863.44

376		C₅₁H₆₃N₅O₈	874.07

377		C₅₄H₆₈N₆O₇	913.15

378		C₅₀H₆₁N₅O₈	860.05

379		C₄₉H₅₄N₄O₈	826.98

380		C₄₈H₅₅BrN₄O₇	879.88

381		C₆₃H₇₂N₄O₁₄	1109.26

382		C₄₆H₅₄N₂O₇S	779

383		C₅₂H₆₄N₂O₁₂S	941.14

384		C₅₂H₆₄N₂O₁₂S	941.14

385		C₅₅H₆₈N₂O₁₂S	981.2

386		C₅₅H₆₈N₂O₁₂S	981.2

387		C₅₈H₆₆N₂O₁₄S	1047.21

388		C₅₈H₆₆N₂O₁₄S	1047.21

389		C₄₆H₅₄N₂O₇S	779

390		C₅₅H₆₈N₄O₉S	961.21

391		C₄₆H₅₅N₂O₁₀PS	858.98

392		C₄₆H₅₇N₂O₁₆P₃S	1018.93

393		C₅₄H₆₆N₄O₉S	947.19

394		C₄₈H₅₅ClN₂O₈S	855.48

395		C₅₀H₆₃N₃O₈S	866.12

396		C₅₃H₆₈N₄O₇S	905.19

397		C₄₉H₆₁N₃O₈S	852.09

398		C₄₈H₅₄N₂O₈S	819.02

399		C₄₇H₅₅BrN₂O₇S	871.92

400		C₆₂H₇₂N₂O₁₄S	1101.31

401		C₄₉H₅₄N₂O₈	798.96

402		C₅₅H₆₄N₂O₁₃	961.1

403		C₅₅H₆₄N₂O₁₃	961.1

404		C₅₈H₆₈N₂O₁₃	1001.17

405		C₅₈H₆₈N₂O₁₃	1001.17

406		C₆₂H₆₈N₂O₁₅	1081.21

407		C₆₂H₆₈N₂O₁₅	1081.21

408		C₅₀H₅₆N₂O₈	812.99

409		C₅₈H₆₈N₄O₁₀	981.18

410		C₄₉H₅₅N₂O₁₁P	878.94

411		C₄₉H₅₇N₂O₁₇P₃	1038.9

412		C₅₇H₆₆N₄O₁₀	967.15

413		C₅₁H₅₅ClN₂O₉	875.44

414		C₅₃H₆₃N₃O₉	886.08

415		C₅₆H₆₈N₄O₈	925.16

416		C₅₂H₆₁N₃O₉	872.06

417		C₅₁H₅₄N₂O₉	838.98

418		C₅₀H₄₅BrN₂O₈	891.88

419		C₆₅H₇₂N₂O₁₅	1121.27

420		C₄₇H₅₈N₂O₁₀	810.97

421		C₄₁H₄₇ClO₉	719.26

422		C₄₂H₅₃NO₉	715.87

423		C₄₁H₄₆O₉	682.8

424		C₄₀H₄₇BrO₈	735.7

425		C₄₀H₄₉NO₇	655.82

426		C₄₁H₄₄O₁₀	696.78

427		C₄₂H₄₆O₁₀	710.87

428		C₄₆H₅₂O₁₀S	796.96

429		C₃₉H₄₅N₃O₇	667.79

430		C₄₄H₅₅NO₉S	773.97

431		C₄₂H₅₁NO₉S	745.92

432		C₄₀H₄₆N₄O₇	694.82

433		C₄₀H₄₅NO₇	651.79

434		C₄₂H₄₆N₂O₇	690.82

435		C₄₉H₅₈N₃O₉S	862.04

436		C₄₂H₄₈N₆O₆	732.87

437		C₄₇H₅₈N₄O₈	839.05

438		C₄₅H₅₄N₄O₈S	811

439		C₄₃H₄₉N₇O₆	759.89

440		C₄₃H₄₈N₄O₆	716.86

441		C₄₅H₄₉N₅O₆	755.9

Preparation of Injection

Example 442

Preparation of Injection 1

Compound 9 (example 9) 5.0 g, ethanol 600 ml, 1,2-propanediol 600 ml and Tween 80 100 ml were dissolved and the injection water was added up to total volume of 5000 ml. The solution was filtered with 0.22 μm membrane filter and sterilized for 30 min at 100° C. to obtain 1000 preparation of injection 5 mg/5 ml.

Example 443

Preparation of Injection 2

Compound 2 (example 2) 8.0 g, DMSO 50 ml, 1,2-propanediol 100 ml and Tween 80 100 ml were dissolved and the injection water was added up to total volume of 5000 ml. The solution was filtered with 0.22 μm membrane filter and sterilized 30 min at 100° C. to obtain 1000 preparation of injection 8 mg/5 ml.

Biological Activity

Example 444

In Vitro Anti-Cancer Cell Experiment

Methods

a. Cell lines: Human pancreatic cancer cell line Panc-1, human colorectal cancer cell line HT₂₉and human lung cancer cell line NCI—H₄₆₀; the medium: s DMEM (Gibco BRL), containing 10% fetal calf serum (Gibco BRL) and 2 mM L-glutamine (Gibco BRL).

b. Test samples: example compounds 5, 9, 10, 22 and 24. The samples were dissolved in dimethyl sulfoxide (DMSO, Sigma, United States) and medium was added to the final concentration of 0.5%. Cisplatin was as positive control of (CDDP, purity 96%, from Kunming Institute of Precious Metals).

c. Method: cells were digested with trypsin and dispersed into single cells in the medium containing penicillin (25 U/ml) and streptomycin (25 μg/ml). The cells were seeded in 96-well culture plates (Corning Incorporated), at 37° C., in a humidified atmosphere with 5% CO₂present for 24 hours. The culture medium was removed, 1-100 μm test compounds were added, cultured for 48 hours. Culture medium was removed and thiophene Wow blue (MTT, USA Sigma products) was added. The result was assayed by SK601-based microplate reader (Japan Seikagaku company's products), 570 nm/630 nm optical density (OD).

Calculation of cell viability: (Experimental group OD/control OD)×100%; Positive control CDDP was treated in the same way.

Results

Inhibition of colorectal cancer: as shown in table 2 five test compounds 5, 9, 10, 22, and 24 showed anti-proliferative effect on HT₂₉. Example compounds 9 and 22 showed significant effect of anti-proliferate on HT₂₉at low IC₅₀(the compound concentration producing 50% inhibition of colony formation) values, respectively, 1.03 μg/ml (P<0.05) and 3.62 μg/ml (P<0.05) than conventional 5-FU and Cisplatin.

Inhibition of pancreatic cancer: as shown in table 2 five test compounds 5, 9, 10, 22, and 24 showed anti-proliferative effect on Panc-1. Example compounds 22 showed anti-proliferative effect on Panc-1 at IC₅₀values 3.26 μg/ml (P<0.05) close to conventional 5-FU.

Inhibition of lung cancer: as shown in table 2 five test compounds showed anti-proliferative effect on NCI—H₄₆₀. Example compounds 9 and 22 showed significant effect of anti-proliferate on NCI—H₄₆₀at low IC₅₀(the compound concentration producing 50% inhibition of colony formation) values, respectively, 6.18 μg/ml (P<0.05) and 4.73 μg/ml (P<0.05) than conventional 5-FU.

TABLE 2

IC₅₀(nM)

	Example	HT₂₉	MCF7	Panc-1	NCI-H₄₆₀

Compound 9	1.03	2.28	3.4	3.38
Compound 22	3.62	6.94	3.26	4.89
Compound 5	35.62	19.26	5.23	7.73
Compound 10	38.33	56.32	17.6	17.25
Compound 24	54.12	44.23	26.8	13.65
CDDP	3.69	3.92	2.17	5.40
5-FU	14.36		3.33

Example 445

Efficacy Studies of Gambogic Acid Glycoside Analogs in Mice

Test samples: example compounds 5, 9, 10, 11, 13, 18, 19, 22, 24, 35 and 306.

Test animals: Kunming kinds of healthy mice (19-21 g), 10 mice (5 male and 5 female)/group, from Beijing Institute of Military Medical Sciences Animal Center.

Tumor strains: mice sarcoma S₁₈₀for ascites passaged from Beijing Academy of Military Medical Institute of Pharmacology.

Methods

Xenografts cultured S₁₈₀tumor cells were implanted subcutaneously into the flank region of mice and tumors were allowed to grow to the desired average size of 100 mg. The mice were randomized into control and treatment groups with 10 mice per group. The control group was injected with the vehicle used to dissolve the drug. Other groups received the test compounds (example compound 5, 9, 10, 11, 13, 18, 19, 22, 24, 35, 306 and positive group, cyclophosphamide (CTX) and 5-fluorouracil (5-FU)) at the dose and schedule as indicated in Table VI. Injections were I.V. via the tail vein. Tumor measurements were taken every other day 20% tumor growth inhibition which was not statistically significant.

Results

The in vivo experimental data showed anti-tumor efficacy of example compound 9, 22, 24 and 35 are statistically significant.

TABLE 3

Growth Inhibition of S₁₈₀sarcoma

The

Inhibition

Example

route

body Weight (g)

Tumor

rate

Compound	of ad.	Before ad.	After ad.	weight (g)	(%)

Control	—	23.09 ± 1.37	28.77 ± 3.17	2.02 ± 0.37	—
CTX	iv	21.48 ± 1.60	26.32 ± 3.58	1.02 ± 0.88	46.5*
5-FU	iv	22.59 ± 1.46	28.55 ± 2.38	1.18 ± 0.49	42.8*
Compound 5	iv	21.53 ± 1.77	27.39 ± 2.91	1.08 ± 0.63	45**
Compound 9	iv	20.53 ± 1.16	23.58 ± 1.86	0.56 ± 0.13	70.21**
Compound 10	iv	20.32 ± 1.22	25.12 ± 4.64	1.24 ± 0.73	39.36*
Compound 11	iv	19.92 ± 1.47	26.30 ± 3.62	1.35 ± 0.59	31.01*
Compound 13	iv	21.76 ± 1.93	27.59 ± 2.52	1.06 ± 0.70	45**
Compound 18	iv	20.16 ± 0.90	27.37 ± 3.92	1.42 ± 0.52	25.26
Compound 19	iv	20.15 ± 0.88	25.89 ± 2.06	1.46 ± 0.58	25
Compound 22	iv	19.34 ± 0.81	25.77 ± 2.33	0.88 ± 0.37	53.19**
Compound 24	iv	20.71 ± 1.75	27.61 ± 2.89	0.65 ± 0.37	62.87**
Compound 35	iv	20.08 ± 1.92	26.86 ± 1.81	0.78 ± 0.33	59.25**
Compound 306	iv	20.75 ± 1.33	26.98 ± 3.02	1.29 ± 0.49	36.77*

Before ad.: before administration;
After ad.: after administration
*P < 0.01: compared with the control group significantly difference;
** p < 0.001: compared with the control group was very significant difference.
Inhibition rate more than 40% of the sample was statistically significant better than control group.

Claims

1. A compound of the formula I, II, III:

or stereoisomers, tautomers, prodrug, pharmaceutically acceptable salts, complex salts or solvates thereof, wherein:

The dotted lines are optionally substituted single bonds, optionally substituted double bond or a optionally substituted heterocyclic group containing carbon, oxygen, sulfur or nitrogen element;

Ring A, ring B or/and ring C is 4-10 membered saturated or/and unsaturated aliphatic ring aliphatic heterocycle or aryl heterocycle.

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁or/and R₁₂is, independently at each occurrence, optionally substituted substituent of glycosyl, optionally substituted multi-hydroxyl, amino acid, acyloxy, phosphoric acid oxy, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy, thiol, substituted thiol, aliphatic or cyclic containing primary amine secondary amine or/and tertiary amine or substituted primary amine, substituted secondary amine or substituted tertiary amine, where contains optionally substituted one or combination;

Substituent containing oxygen, sulfur, nitrogen or phosphorus element is, independently at each occurrence, optionally substituted one or combination of saturated, unsaturated

C_1-10alkyl, optionally substituted 1-4 double bond, optionally substituted triple bond, optional substituent of saturated or unsaturated C_1-10alicyclic, arylcyclic and heterocyclic group, where contains a cycle or combination of oxygen, sulfur, nitrogen or phosphorus element, saturated or unsaturated 3-7 membered alicycle, aryl cycle, multi-cycle, aliphatic heterocycle, aryl heterocycle or fused heterocycle;

wherein:

X₁and X₂are, independently at each occurrence, C═O, C═Rb—Ra, CHOH, CHORb, CHRb or substituent, where Rb contains, independently at each occurrence, one or combination of C, N or P element; Ra is H, H₂, optionally substituted straight-alkyl, optionally substituted branched-alkyl, C_1-10optionally substituted saturated alkyl, optionally substituted 1-4 double bond, optionally substituted 1-4 triple bond, optionally substituted unsaturated alkyl, optionally substituted saturated or unsaturated alicyclic, optionally substituted arylcyclic, optionally substituted aryl or optionally substituted 3-7 membered heterocyclic, optionally substituted aryheterocyclic, fused heterocyclic group where contains hydroxyl, halogen, oxygen, nitrogen, sulfur or phosphorus element;

wherein:

Cyclized cyclic substituent is, independently at each occurrence, formed a new one or a combination of A-ring between C-4 and C-6, B-ring between C-6 and C-8, C-ring between C-8 and C-10 positions;

R₁₂, R₁, R₂, R₅, R₆, R₈, R₉, R₁₀, R₁₁or/and R₁₂is, independently at each occurrence, H, halogen or XRa; where XRa is unsubstituted or substituted group containing C, O, S, Se, N, and/or P element. R₃is XaRa electrophilic substituent, where Xa is, independently at each occurrence, unsubstituted or substituted group containing C, S, P, and/or Si element.

R₄is, independently at each occurrence, optional substituent of 1-8 glycosyl, multi-hydroxyl, substituted multi-hydroxyl, 1-5 amino acid, 1-4 phosphate, acyloxy, phosphoric, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy, alkyl, alicyclic, aryl cyclic, aliphatic heterocyclic oxyl or aryl heterocyclic oxyl group containing oxygen, sulfur, nitrogen or phosphorus element, where glycosyl, multi-hydroxyl, amino acid, acryloxy, phosphoryloxy, sulfonyloxy, alkoxy, aryloxy, heterocyclic oxy and substituent is the same as above.

wherein:

C_3-8Saccharide is independently at each occurrence, optionally substituted C₃saccharide, optionally substituted C₄saccharide, optionally substituted C₅saccharide, optionally substituted C₆saccharide, optionally substituted C₇saccharide, optionally substituted C₈saccharide, optionally substituted hydroxyl saccharide, optionally substituted amino saccharide, optionally substituted deoxy saccharide, optionally substituted sulfuric acid saccharide, optionally substituted hetero-element saccharide and/or its glycoside.

R₇is H or XbRa; Xb is, independently at each occurrence, optional substituent containing H, C, O or N element.

wherein:

When X₁and/or X₂is C═O, C═Rb—Ra, CHOH, CHORb or CHRb, X₁and X₂are the same or different substituents; when Rb is C, N or P element, Ra is, independently at each occurrence, optionally substituted formation of olefin, alkane, halogenated hydrocarbon, alcohol, ether, oxime, hydrazone or substituted said groups.

A bromo compound at 11-position is selected, independently at each occurrence, from:

gambogic acid, methyl gambogate, ethyl gambogate, gambogyl morpholine, gambogyl.

2. A compound according to the claim 1, wherein:

A compound with A-ring, B-ring or/and C-ring cyclized respectively between 4- and 6-position, 6- and 8-position and 8- and 10-position of gamboge acid is selected, independently at each occurrence, from the example 1 to example 441 and following list but not limiting, of the method and composition of the present invention:

Fused A-ring was formed between 4- and 6-position of gambogate acid analogs, methyl pyrano[4,3,2-d,e]gambogate-5(4H)one, methyl-5-ketone-4,7,12-trihydropyrano[4″,3″,2″:4′,5′,6′]gambogate[10′,9′,8′:4,5,6]pyrimidino[3,2-a]imidazole, methyl-5-ketone-4,7,12-trihydropyrano[4″,3″,2″:4′,5′,6]gambogate[10′,9′,8′:4,5,6]pyrimidino[3,2-b]triazolo(1,2,4), methyl-5-ketone-4,7,10-trihydropyrano[4′,3′,2′:4,5,6]gambogate[10,9,8:d,e]-8-amino-9-cyanopyrimidine, methyl-5-ketone-4,10-dihydropyrano[4′,3′,2′:4,5,6]gambogate[10,9,8:d,e]-8-amino-9-cyanopyrimidine, methyl-5-ketone-4,10-dihydropyrano[4′,3′,2′:4,5,6]gambogate[10,9,8:d,e]-8-amino-9-cyanopyran, methylpyrano[4,3,2-d,e]-5-ketone-4,13-dihydrobenzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-ketone-4,7,12-trihydro pyrano[4″,3″,2″:4′,5′,6′]gambogate[10′,8′:2,3,4]thiazepino[1,4][6,7-a]benzene, methyl-5-ketone-4,8,14,15-tetrahydropyrano[4″,3″,2″:4′,5′,6′]gambogate[10′,9′,8′:4,5,6]pyrano[3,2-b]indanone-1, methyl-5-ketone-4,14,15-trihydropyrano[4″,3″,2″:4′,5′,6]gambogate[10′,9′,8′:4,5,6]pyrido[3,2-b]indanone-1,methyl-5-ketone-4,8,9-trihydropyran-9-(1-H-3-amino-1,2,4-triazol-1-yl)pyrano[4,3,2:d,e]gambogate, methyl-5-ketone-4,8,9-trihydropyran-9-dicyanomethyl-pyrano[4,3,2:d,e]gambogate, methyl-5-ketone-8,9-dihydro-9-malonicamidoximepyrano[4,3,2-d,e]gambogate, methyl-5-ketone-4,7,11-trihydrogenpyrano[4,3,2-d,e]gambogate[2,4-b,c]-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-bisene, methyl-4,5-dionepyrano[4,6-b,c]gambogate, methyl-4,6-dioneheptlactono[4,6-bc]gambogate.

Fused B-ring was formed between 6- and 8-position of gambogate acid analogs, methyl-6-H-oxazino[1,3][6,5,4-f,g]gambogate, methyl-6,8,9-trihydrogen-9-(1-H-3-amino-1,2,4-triazol-1-yl)oxazino[1,3][6,5,4-f,g]gambogate, methyl-6,8,9-trihydrogen-9-dicyano-methyleviltriazino[1,3][6,5,4-f,g]gambogate, methyl-8,9-dihydro-9-malonicamidoxime-oxazino[1,3][6,5,4-f,g]gambogate, methyl-6,8,9-trihydrogen-9-morpholinylhydrogen-1,3-oxazino[6,5,4-f,g]gambogate, methyl-6,8,9-trihydrogen-9-(4-methylpyrazine)-1,3-oxazino[6,5,4-f,g]gambogate, methyl-5-H-1,3-oxazino[6,5,4-f,g]gambogate.

Fused C-ring were formed between 8- and 10-position of gambogate acid analogs, methyl-6,11-dihydroimidazo[1′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-alloglycosyl)imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-glucosyl)imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d]-1,3-dioxane-9-oxyimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-alloglycosyl)benzoylimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-glucosyl)benzoylimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-methylimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]imidazo[2′1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-O-phosphorylimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-oxygentriphosphorylimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-[4-(4-methylpiperazin-1-yl)-3-oxo-propionyl]imidazolo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-chloroacetyl)imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-hydroxyethylamino)ethylimidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-hydroxyamino)methyl imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(bromomethyl)imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate methyl-6,11-dihydro-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxygenhexacyclo-9-oxy)ethaneformyl)imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydrogentriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-alloglycosyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-glucosyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-alloglycosyl)benzoicacyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-oxo-D-glucosyl)benzoyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate methyl-6,11-dihydro-5-methyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-[4-(4-methylpiperazine-1-yl)-4-oxo-dibutyryl]triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-oxygenphosphoryltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-triphosphoryloxygentriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-[4-(4-methylpiperazin-1-yl)-3-oxo-propionyl]triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-chloroacetyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-hydroxyethylamino)ethyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-(4-methylpiperazine-1-yl)-ethyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(2-hydroxyamino)methyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-bromomethyl-triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,11-dihydro-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-O-D-alloglycosyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-O-D-glucose)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethyl-hexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzoyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)benzoyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-oxygentriphosphoryl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-3-oxo-propionyl]-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxy)ethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-(4-methyl piperazin-1-yl)ethyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyamine) methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-bromomethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d](1,3)dioxane-9-oxy)benzoyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzoyl-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)benzoyl-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5,6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxo-butyryl]-6-dimethyl-7-amino-8-cyano-9-Hpyrido[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-O-triphosphoryl-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-3-oxo-propionyl]-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-(4-methylpiperazin-1-yl)-ethyl)-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyamino)methyl-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-bromomethyl-6-dimethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-6-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate, methyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethyl-hexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzoicacyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)benzoyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-methyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-[4-(4-methyl-piperzin-1-yl)-4-oxobutyryl]-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-O-triphosphorusacyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-3-oxo-propionyl]-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(2-(4-methylpiperazin-1-yl)-yl)-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)methyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-bromomethyl-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexandropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-7-amino-8-cyano-9-H-pyrano[6,5,4-h,i]gambogate, methyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(4-O-D-alloglycosyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)-13-hydrogenbenzeno[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethyhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(4-O-D-alloglycosyl-) benzoyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(4-O-D-glucose)benzoyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-methyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-β-triphosphoryl-13-hydrogenbenzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazine-1-yl)-3-oxo-propionyl]-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(2-(4-methylpiperazin-1-yl)-ethyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)methyl-13-H-benzo[d]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(bromomethyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxygenyl)benzoyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate, methyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(4-oxo-D-glucose)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethylhexa hydropyrano[3,2-d][1,3]dioxane-9-oxy)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(4-O-glycosyl-D-allo) benzoyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)benzeneformyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-methyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, 5-O-phosphoryl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-O-triphosphorylcholine-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-[4-(4-methylpiperzin-1-yl)-3-oxopropionyl]-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(2-chloroacetyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(2-hydroxyethylamino)methyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(bromomethyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethyl hexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate, methyl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)-7,13,14-trihydrogen-indanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)-7,13,14-tri-hydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzeneformyl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)-benzoyl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-methyl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-O-triphosphoryl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperzin-1-yl)-3-oxo-propionyl]-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyamino)methyl-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(bromomethyl-)-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-7,13,14-trihydrogenindanone-1′[3′,2′:2,3]pyrano[6,5,4-h,i]gambogate, methyl-12,13-dihydro-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-allo-glycosyl)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-12,13-dihydro-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzoyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)benzoyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-methyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazine-1-yl)-4-oxobutyryl]-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-12,13-dihydroindeneketone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate methyl-5-O-triphosphoryl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazine-1-yl)-3-oxo-propionyl]-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-12,13-dihydro-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)methyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(bromomethyl-)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-12,13-dihydrogenindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazole)gambogate, methyl-6-(4-oxo-D-alloglycosyl)-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-(4-oxo-D-glucose)-9,10-dihydroxy-10-(1-H-3-amino-1,2,4-triazole-1-yl)gambogate, methyl-6-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-(4-oxo-D-alloglycosyl)benzoyl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazole-1-yl)gambogate, methyl-6-(4-oxo-D-glucosyl)benzoyl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-methyl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazole)gambogate, methyl-6-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-O-phosphoryl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-O-triphosphoryl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazole-1-yl)gambogate, methyl-6-[4-(4-methylpiperazin-1-yl)-3-oxo-propionyl]-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-(2-chloroacetyl)-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-(2-hydroxyethylamino)ethyl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-(2-(4-methylpiperzin-1-yl)-ethyl)-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazole)gambogate, methyl-6-(2-hydroxyamino)methyl-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-6-(bromomethyl)-9,10-dihydro-10-(1-H-3-amino-1,2,4-tritriazole-1-yl)gambogate, methyl-6-(4-(7,8-dihydroxy-4,4-dimethyl-hexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-9,10-dihydro-10-(1-H-3-amino-1,2,4-triazol-1-yl)gambogate, methyl-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(4-oxo-D-alloglycosyl)-9,10-dihydro-10-dicyanidegambogate, methyl-6-(4-oxo-D-glucose)-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(4-oxo-D-alloglycosyl)benzoyl-9,10-dihydro-10-dicyanomethylgambogate, 6-(4-oxo-D-glucosyl)benzoyl-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-methyl-9,10-dihydro-10-dicyanidegambogate, methyl-6-[4-(4-methylpiperazin-1-yl)-4-oxobutyryl]-9,10-dihydro-10-dicyanomethylgambogate, 6-O-phosphorylcholine-9,10-dihydro-10-dicyanomethyl-gambogate, 6-O-triphosphoryl-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-[4-(4-methyl-piperazine-1-yl)-3-oxo-propionyl]-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(2-chloroacetyl)-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(2-hydroxyethylamino)ethyl-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(2-(4-methylpiperazin-1-yl)ethyl)-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(2-hydroxyamino)methyl-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(bromo-methyl-)-9,10-dihydro-10-dicyanomethylgambogate, methyl-6-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxygen)benzoyl)-9,10-dihydro-10-dicyanomethylgambogate, methyl-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-(4-O-D-allosugar)-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-(4-oxo-D-glucose)-9,10-dihydro-10-malonylaminooximegambogate, methyl-6-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-(4-oxo-D-alloglycosyl)-benzoyl-9,10-dihydro-10-malonylamidoximegambogate, methyl-6-(4-oxo-D-glucose)benzoicacyl-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-methyl-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-[4-(4-methylpiperazine-1-yl)-4-oxobutyryl]-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-O-phosphoryl-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-O-triphosphoryl-9,10-dihydro-10-malonic-amidoximegambogate, methyl-6-[4-(4-methylpiperazine-1-yl)-3-oxopropionyl]-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-(2-chloroacetyl)-9,10-dihydro-10-malonylamidoximegambogate, methyl-6-(2-hydroxyethyl)ethyl-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-(2-(4-methylpiperazin-1-yl)ethyl)-9,10-dihydro-10-malonylamidoximegambogate, methyl-6-(2-hydroxyethylamino)methyl-9,1-aminodihydro-10-malonicamidoximegambogate, methyl-6-methyl-bromide-9,10-dihydro-10-malonicamidoximegambogate, methyl-6-(4-(7,8-dihydroxy-4,4-dimethyl-hexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-9,10-dihydro-10-malonicamidoximegambogate, methyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(4-oxo-D-glucose)-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethyl-hexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzoyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)benzoyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-methyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-[4-(4-methylpiperazine-1-ly)-4-oxobutyryl]-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-O-phosphoryl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-O-triphosphoryl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-[4-(4-methyl piperazine-1-yl)-3-oxo-propionyl]-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(2-chloroacetyl)-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1) nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(2-hydroxyamino)ethyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(2-(4-methyl-piperazin-1-yl)-ethyl)-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)methyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-bromomethyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl-10-H-1′,5′,7′,9′-tetrazabicyclo(4,2,1)nonyl-3′,7′-dieno[2,4-h,i]gambogate, methyl-1-cyclopropyl-6-fluoro-4-oxo-7-[4-(9,10-dihydro-10-gambogate)piperazinyl]-1,4-dihydroquinoline-3-carboxylic acid, methyl-1-cyclopropyl-6-fluoro-4-oxo-7-[4-(6-(4-oxo-D-alloglycosyl)-9,10-dihydro-10-gambogate)piperazinyl]-1,4-dihydroquinoline-3-carboxylic acid, methyl-1-cyclopropyl-6-fluoro-4-oxo-7-[4-(6-(4-O-D-glucose)-9,10-dihydro-10-gambogate)piperazinyl]-1,4-dihydroquinoline-3-carboxylic acid, methyl-1-cyclopropyl-6-fluoro-4-oxo-7-[4-(6-methyl-9,10-dihydro-10-gambogate)piperazinyl]-1,4-dihydroquinoline-3-carboxyl acid, methyl-6-aminoethyl-12-hydrogenindanone-1′-[3″,2″:2′,3′]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyridino[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-alloglycosyl)benzoyl-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyridino[6,5,4-h,i]gambogate, methyl-5-(4-oxo-D-glucosyl)benzoyl-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-methyl-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperzin-1-yl)-4-oxobutyryl]-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-O-phosphoryl-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-O-triphosphoryl-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-[4-(4-methylpiperzin-1-yl)-3-oxopropionyl]-6-aminoethyl-12-H-indanone-1′-[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-chloro-acetyl)-6-aminoethyl-12-hydrogenindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)ethyl-6-aminoethyl-12-H-indanone-1′-[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-(4-methylpiperzin-1-yl)ethyl)-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(2-hydroxyethylamino)methyl-6-amino-ethyl-12-H-indanone-1′ [3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-ketone-4,13-dihydro-7-aminoethylpyrano[4″,3″,2″:4′,5′,6′]gambogate[10′,9′,8′:4,5,6]pyrido[3,2-b]indanone-1, methyl-5-bromomethyl-6-aminoethyl-12-H-indanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-6-aminoethyl-12-hydrogenindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate, methyl-6-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy))-9,10-dihydro-10-morpholinylgambogate, methyl-6-[4-(4-methyl-piperazine-1-yl)-4-oxobutyryl]-9,10-dihydro-10-morpholinylgambogate, methyl-6-[4-(4-methylpiperazine-1-yl)-3-oxopropionyl]-9,10-dihydro-10-morpholinylgambogate, methyl-6-(2-chloroacetyl)-9,10-dihydro-10-morpholinylgambogate, methyl-6-(2-hydroxyethylamino)ethyl-9,10-dihydro-10-morpholinylgambogate, methyl-6-(2-(4-methylpiperzin-1-yl)ethyl)-9,10-dihydro-10-morpholinylgambogate, methyl-6-(2-hydroxyethylamino)methyl-9,10-dihydro-10-morpholinylgambogate, methyl-5-ketone-4,8,9-trihydrogen-pyrano[4,3,2-d,e]-9-morpholinylgambogate, methyl-5-(bromomethyl)-9,10-dihydro-10-morpholinylgambogate, methyl-9,10-dihydro-10-morpholino-6-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)gambogate, methyl-9,1,0-dihydro-10-(4-methylpyrazine)-6-(7,8-dihydroxy-4,4-dimethylhexahydro pyrano[3,2-d][1,3]dioxane-9-oxy)gambogate, methyl-9,10-dihydro-10-(4-methyl-pyrazinyl)-6-[4-(4-methylpiperazine-1-yl)-4-oxobutyryl]gambogate, methyl-9,10-dihydro-10-(4-methylpyrazinyl)-6-[4-(4-methylpiperazinyl-1-yl)-3-oxopropionyl]gambogate, methyl-6-(2-chloroacetyl)-9,10-dihydro-10-(4-methylpyrazinyl)gambogate, methyl-6-(2-hydroxyethylamino)ethyl-9,10-dihydro-10-(4-methylpyrazinyl)gambogate, methyl-6-(2-(4-methylpiperzin-1-yl)-ethyl)-9,10-dihydro-10-(4-methylpyrazinyl) gambogate, methyl-6-(2-hydroxyethylamino)methyl-9,10-dihydrogen-10-(4-methyl pyrazinyl)gambogate, methyl-5-ketone-4,8,9-trihydrogen-9-(4-methylpyrazinyl)pyrano[4,3,2-d,e]gambogate, methyl-6-(bromomethyl)-9,10-dihydro-10-(4-methylpyrazinyl) gambogate, methyl-9,10-dihydro-10-(4-methylpyrazinyl)-6-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)gambogate, 6,11-dihydro-triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxyl-amine, 6,11-dihydro-5-(4-oxo-D-alloglycosyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxyl-amine, 6,11-dihydro-5-(4-oxo-D-glucose)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydrogen-5-(7,8-dihydroxy-4,4-dimethylhexahydro-pyrano[3,2-d][1,3]dioxane-9-oxy)triazole[1,2,4][3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-(4-aloroxygen-D-glycosyl)benzoyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-(4-oxo-D-glucosyl)benzoyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-methyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-[4-(4-methylpiperazine-1-yl)-4-oxobutyryl]triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxyltriethylamine, 6,11-dihydro-5-O-phosphoryl-triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-oxygentriphosphoryl triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxyl-amine, 6,11-dihydro-5-[4-(4-methylpiperazine-1-yl)-3-oxopropionyl]triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-(2-chloroacetyl) triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-(2-hydroxyethylamino)ethyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogate-hydroxylamine, 6,11-dihydro-5-(2-(4-methylpiperazine-1-yl)ethyl)triazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,11-dihydro-5-(2-hydroxyamino) methyltriazolo(1,2,4)[3′,2′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-ketone-4,7,12-trihydropyrano[4″,3″,2″:4′,5′,6′]dihydrohydroxyethylaminogambogate[10′,9′,8′:4,5,6]pyrimidino[3,2-b]-1,2,4-triazole, 5-(bromomethyl)-1,2,4-triazolo[3′,2′:2,3]pyrimidino[6,5,4-h,i]-6,11-dihydro-hydroxyethylaminogambogate, 5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)[1,2,4]triazolo[3′,2′:2,3]pyrimidino[6,5,4-h,i]-6,11-dihydro-hydroxygambogate, 7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-alloglycosyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-gamino glucose)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogate-hydroxylamine, 5-(4-oxo-D-alosglycosylation)benzoyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxyl-amine, 5-(4-oxo-D-glucosyl)benzoyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-[4-(4-methylpiperzin-1-yl)-4-oxobutyryl]-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-O-phosphoryl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-O-triphosphoryl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-[4-(4-methylpiperzin-1-yl)-3-oxopropionyl]-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-chloroacetyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-hydroxyethylamino)ethyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxyl-amine, 5-(2-(4-methylpiperzin-1-yl)ethyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-hydroxyethylamino)methyl-7-amino-8-cyano-9-H-pyridino[6,5,4-h,i]gambogatehydroxylamine, 5-ketone-4,7,10-triplehydrogenpyrano[4′,3′,2′:4,5,6]hydroxyethylamino gambogate[10,9,8:d,e]8-amino-9-cyanopyrimidine, 5-bromo-methyl-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-(7,8-dihydroxy-4,4-dimethylhexa-hydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-7-amino-8-cyano-9-H-pyrido[6,5,4-h,i]gambogatehydroxyethylamine, 13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(4-aloroxygen-D-glycosyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-glucose)-13-H-benzo[d′]imidazo[2′,1:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-13-H-benzo[d]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-alloglycosyl)benzoyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate hydroxylamine, 5-(4-oxo-D-glucosyl)-benzoyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-methyl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-[4-(4-methylpiperzin-1-yl)-4-oxobutyryl]-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxyl-amine, 5-O-phosphoryl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxyl-amine, 5-O-triphosphoryl-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-[4-(4-methylpiperazine-1-yl)-3-oxopropionyl]-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(2-chloroacetyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(2-hydroxyethylamino)ethyl-13-H-benzo[d′]imidazo[2,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(2-(4-methylpiperzin-1-yl)ethyl)-13-H-benzo[d′]imidazolo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 5-(2-hydroxyethyl)methyl-13-H-benzeno[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate-hydroxylamine, pyrano[4,3,2-d,e]-5(4H)-ketone-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogateaminohydroxylethylamine, 5-(bromomethyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogate glycolsylamine, 5-(4-(7,8-dihydroxy-4,4-dimethylhexa-hydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-13-H-benzo[d′]imidazo[2′,1′:2,3]pyrimidino[6,5,4-h,i]gambogatehydroxylamine, 6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxyl-amine, 5-(4-oxo-D-allosugar)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(4-O-D-glucose)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 6,12-dihydro-5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-phenoxy)benzeno[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(4-oxo-D-alloglycosyl)benzoyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(4-oxo-D-glucose)benzoyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-methyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-[4-(4-methyl-piperzin-1-yl)-4-oxobutyryl]-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogate-hydroxylamine, 5-O-phosphoryl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-O-triphosphoryl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-[4-(4-methyl-piperzin-1-yl)-3-oxopropionyl]-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(2-chloroacetyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(2-hydroxy-ethylamino)ethyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxyl-amine, 5-(2-(4-methylpiperzin-1-yl)ethyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(2-hydroxyethylamino)methyl-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-ketone-4,7,12-trihydropyrano[4″,3″,2″:4′,5′,6′]gambogatehydroxylamino[10′,8′:2,3,4]thiazepino[1,4][6,7-a]benzene, 5-(bromo-methyl-)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylamine, 5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-6,12-dihydrobenzo[b][1,4]thiazepino[4,3,2-h,i]gambogatehydroxylethylamine, 12,13-dihydro-indanone-1′-[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-glucose)-12,13-dihydroindanone-1′-[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-alloglycosyl)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-oxo-D-alloglycosyl)benzoyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogate-hydroxylamine, 5-(4-oxo-D-glucosyl)benzoyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-methyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-[4-(4-methylpiperzin-1-yl)-4-oxobutyryl]-12,13-dihydroindanone-1′ [3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-O-phosphoryl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-O-triphosphoryl-12,13-dihydroindanone-1′ [3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-[4-(4-methylpiperzin-1-yl)-3-oxopropionyl]-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-chloroacetyl)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-hydroxyethylamino)ethyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-(4-methyl-piperine-1-yl)ethyl)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(2-hydroxyethylamino)methyl-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-ketone-4,14,15-trihydropyrano[4″,3″,2″:4′,5′,6′]gambogatehydroxylamino[10′,9′,8′:4,5,6]pyrido[3,2-b]indanone-1,5-(bromo-methyl)-12,13-dihydroindanone-1′[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, 5-(4-(7,8-dihydroxy-4,4-dimethylhexahydropyrano[3,2-d][1,3]dioxane-9-oxy)benzoyl)-12,13-dihydro-indanone-1′-[3′,2′:2,3]pyrido[6,5,4-h,i]gambogatehydroxylamine, methyl-5-[4-(4-methylpiperazine-1-yl)-4-oxobutyryl]gambogate, methyl-5-[4-(4-methylpiperzin-1-yl)-3-oxopropionyl]gambogate, methyl-6-(2-chloroacetyl)gambogate, methyl-5-(2-hydroxyethylamino)ethylgambogate, methyl-6-(2-(4-methylpiperzin-1-yl)ethyl)gambogate, methyl-6-(2-hydroxyamino)gambogate, methyl-4-H-pyrone(5)[4,3,2-d,e]gambogate, methyl-6-(2-bromoethyl)gambogate.

3. A compound according to claim 1, wherein:

4. A compound according to the claim 1, wherein:

A process for the manufacture of a compound of formula I, II, III comprises:

For the preparation of compounds of formula I, II, III with A-ring, B-ring, C-ring and salts thereof in which the reaction of a gambogic acid or analog to introduce A-ring lactone at 4-, 6-position, B-ring at 6-, 8-position, and C-ring at 8-, 10-position forms a bond of C—C, C—O, C—S, C—N or C—P under catalysis at −78° C. to 90° C., wherein;

The reactant selected from 2-ethoxy-1-ethoxy carbon acyl-1,2-dihydroquinoline, 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyl urea hexafluorophosphate, benzotriazole-N,N,N′, N′-tetramethyl urea hexafluoro phosphate, 6-chlorophenyl and triazole-1,1,3,3-tetramethyl urea hexafluoro phosphate, 1-hydroxy-7-azobis benzotriazole, 1-hydroxy-benzotriazole, 3-hydroxy-1,2,3-benzotriazin-4(3H)one, N-hydroxysuccinimide, and triethylamine, Fmoc chloride, acyl succinimide Fmoc, 9-fluorene methanol;

The catalyst selected from palladium, platinum, ruthenium, metal catalyst, organic base or inorganic base, 1-ethyl-3-(3-dimethylpropylamine)carbodiimide, ditertbutyl dicarbonate, bis(2-oxo-3-oxazoline alkyl) times phosphorus chloride, N,N′-carbonyl two pyrrolidine, N,N′-carbonyl bis(1,2,4-triazole), 6-chloro-1-hydroxybenzo triazole, N,N′-dicyclohexyl carbodiimide, 4,5-dicyano imidazole, 3-(diethoxyphosphoryl)oxy-1,2,3-benzotriazine-4-ketone, N,N′-bis isopropyl carbon imide, N,N′-diisopropyl ethylamine, 4-dimethylaminopyridine, 4,4′-dimethoxytriphenyl chloride, 4-(4,6-dimethoxytriazine)-4-methyl morpholine hydrochloride, N,N′-succinimidyl carbonate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride;

The solvent selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexane, toluene, quinoline.

5. A compound according to the claim 1, wherein: For the preparation of compounds of formula I, II, III with A-ring, B-ring, C-ring and salts, the X₁, X₂, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁or/and R₁₂is an amino acid, acyloxy, phosphoric acid, phosphoryloxy, sulfonyloxy, alkoxy, aryloxy, heterocyclicoxy, hydrocarbons, alicyclic, glycosyl, multi-hydroxyl, carboxyl, glucosyl, multi-hydroxyl, alkane, aryl, alicyclic, heterocyclic, heteroarylcyclic or substituent modified by acylation, halogenation; electrophilic substituent at 9-position, nucleophilic substituent at 10-position accompanied by 1,4 addition reaction; allylation at 11-position, 26-position, 31-position or 36-position with a bond of C—C, C—O, C—S, C—N or C—P under catalysis at −78 to 90° C.

6. A method according to the claim 3, wherein:

A method for treating cancer, comprising: administration to a compound of the claim 1 and claim 9, in the range of 0.001 mg/kg-250 mg/kg, a pharmaceutically acceptable salt or prodrug from thereof;

a cancer is selected from the lung cancer, stomach cancer, colon cancer, small cell lung cancer, thyroid cancer, esophageal cancer, pancreatic cancer, endometrial cancer, adrenal cortical carcinoma, head and neck cancer, Osteogenic sarcoma, breast cancer, ovarian cancer, Vail Williams tumors, cervical tumors, testicular cancer, genitourinary cancer, skin cancer, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdomyosarcoma, Kaposi sarcoma, malignant melanoma, malignant pancreatic islet tumors, non-Hodgkin's lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, malignant carcinoid cancer, choriocarcinoma, acute and chronic lymphocytic leukemia, primary macroglobulinemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, or Hodgkin's disease.

7. The method according to claim 3, wherein said compounds is administered together with at least one known cancer, chemotherapeutic and immune agent selected from cyclophosphamide, vincristine, busulfan, vinblastine, cisplatin, carboplatin, mitomycin C, doxorubicin, colchicine, etoposide, paclitaxel, docetaxel, camptothecin, topotecan, arsenic trioxide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2-deoxyuridine, hydroxyurea, thioguanine, melphalan, chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, octreotide, retinoic acid, tamoxifen, doxazocin, terazosin tamsulosin, tamsulosin, fluorine pyridinoline, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, atorvastatin, amprenavir, abacavir, flavonoids pyridinoline, ritonavir, saquinavir, rofecoxib, alanosine, retinal, tretinoin tocoferil, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoro-methyl ornithine, fenretinide, N-4-carboxyphenyl retinamide, genistein, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232, 632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778, 123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine, Valecoxib.

8. A method according to the claim 3, wherein:

a compound for treating, preventing or slowing the progression of neoplasia and cancer, and infection diseases by virus, bacterial or fungi, including bacterial infections and fungal infections of the drug application, which comprises administration together with at least one known chemotherapeutic agent selected from the group consisting of antibacterial and antifungal drugs to a patient in need of such treatment.

9. A compound according to the claim 3, wherein:

the administration may be by oral route, parenteral, subcutaneous, intravenous, intramuscular, intra-peritoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.

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